Next Article in Journal
High-Performance Integrated Virtual Environment (HIVE) Tools and Applications for Big Data Analysis
Next Article in Special Issue
Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs
Previous Article in Journal
Mouse ENU Mutagenesis to Understand Immunity to Infection: Methods, Selected Examples, and Perspectives
Previous Article in Special Issue
The Role of microRNAs in Mitochondria: Small Players Acting Wide
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Genes
Volume 5
Issue 4
10.3390/genes5040926
genes-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Role of MicroRNAs in Diabetic Complications—Special Emphasis on Wound Healing

by
João Moura
1,
Elisabet Børsheim
2,3,4,5 and
Eugenia Carvalho
1,2,3,6,*
1
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal
2
Arkansas Children's Nutrition Center, Little Rock, Arkansas, AR 72202, USA
3
Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
4
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
5
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
6
The Portuguese Diabetes Association (APDP), Lisbon 1250 203, Portugal
*
Author to whom correspondence should be addressed.
Genes 2014, 5(4), 926-956; https://doi.org/10.3390/genes5040926
Submission received: 5 June 2014 / Revised: 5 September 2014 / Accepted: 10 September 2014 / Published: 29 September 2014
(This article belongs to the Special Issue miRNA Regulation)
Browse Figures
Versions Notes

Abstract

:
Overweight and obesity are major problems in today’s society, driving the prevalence of diabetes and its related complications. It is important to understand the molecular mechanisms underlying the chronic complications in diabetes in order to develop better therapeutic approaches for these conditions. Some of the most important complications include macrovascular abnormalities, e.g., heart disease and atherosclerosis, and microvascular abnormalities, e.g., retinopathy, nephropathy and neuropathy, in particular diabetic foot ulceration. The highly conserved endogenous small non-coding RNA molecules, the micro RNAs (miRNAs) have in recent years been found to be involved in a number of biological processes, including the pathogenesis of disease. Their main function is to regulate post-transcriptional gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation, suppression of translation or even gene activation. These molecules are promising therapeutic targets and demonstrate great potential as diagnostic biomarkers for disease. This review aims to describe the most recent findings regarding the important roles of miRNAs in diabetes and its complications, with special attention given to the different phases of diabetic wound healing.

Graphical Abstract

1. Diabetes and Its Complications

The prevalence of diabetes, a chronic metabolic disorder, has been increasing at alarming rates all over the world and is estimated to rise to 552 million adults by 2030 [1,2]. The associated increase in mortality and morbidity makes it one of the major health and socio-economic problems in our society [1,3]. The concurrent overweight and obesity epidemic, due to poor diet and lack of physical activity and interactions with genetic predisposition, greatly affect the prevalence of diabetes [1,2]. Type 2 diabetes mellitus (T2DM), in particular, which used to be predominantly a disease of adults, is now commonly observed at an early age in children and adolescents [1,3]. The increasing incidence of obesity in children and the resultant insulin resistance contributes to the increasing prevalence of T2DM in this population.
T2DM comprises approximately 90% of all diabetic patients and is characterized by hyperglycemia. This is mainly caused by lack of insulin, or loss of insulin sensitivity in the target organs in the presence of normal insulin secretion, or a combination of both. In contrast, type 1 diabetes is characterized by the absolute lack of insulin due to failure of the beta cell. Insulin resistance, which is the impaired ability of insulin to elicit its metabolic effects in the target tissues, particularly, in fat, liver and skeletal muscle, is one of the important causes of T2DM and cardiovascular disease [4,5]. Long-term hyperglycemia can lead to serious macrovascular and microvascular complications. Accelerated atherosclerosis and hypertension, common in diabetic patients, tend to cause macrovascular complications, such as cardiovascular deterioration and ultimately coronary heart disease and stroke [6,7]. On the other hand, microvascular events cause diabetic retinopathy [8,9], a leading cause of blindness in patients, and diabetic nephropathy [10,11], affecting the kidneys with disruption of glomeruli, tubules, vessels and the interstitium, causing impairment in renal function and ultimately leading to end-stage renal disease. In addition, microvascular disease can also cause diabetic neuropathy [3,12,13], affecting in particular the nervous system, ultimately leading to the development of chronic diabetic foot ulcers (DFU), among other complications.
The chronic inflammatory state characteristic of T2DM, leading to its severe chronic complications, can be delayed or even prevented by proper nutrition and regular physical exercise, at an early stage. However, the need to find better and more effective treatment solutions for these long-term complications in patients remains of importance. Several large clinical trials have been performed to address some of these questions [14,15,16]. The results coming from these large studies show that even though glucose-lowering treatment reduces the risk of cardiovascular diseases, the risks of macrovascular and microvascular complications still remain, and the development of new therapeutic strategies is needed. It has been suggested that the main reason these large studies have not been able to show any major impact on lowering the risk for diabetic complications, is that the interventions are implemented too late after the diagnosis of the disease. This is supported by the UKPDS and STENO-2 studies, where treatment of chronic hyperglycemia was undertaken at the early stages of the disease [17,18]. These interventions resulted in lower glycemia and long-term reduction of the risk of macrovascular and microvascular complications. However, most of the currently used therapies are not fully efficacious and therefore, there is an urgent need for a better understanding of the biomolecular mechanisms underlying T2DM development and its complications in order to identify better therapeutic targets.
The highly conserved endogenous small non-coding RNA molecules, micro RNAs (miRNAs or miR) are 18–25 nucleotides in length. They have recently been shown to be involved in the regulation of many key biological functions in both physiological and pathophysiological states, including the maintenance of cellular signaling and the regulation of entire pathways. When the tight miRNA regulation is altered it can lead to serious physiological abnormalities, including chronic diseases, such as diabetes and its complications [19,20,21,22]. Their main function is to regulate post-transcriptional gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or suppression of translation [19,20,21]. These molecules are promising therapeutic targets and demonstrate great potential as diagnostic biomarkers for the different diabetes complications. This review summarizes first the most recent findings regarding the important role of miRNA in the general pathology of diabetic complications, focusing toward the end, on the less studied, diabetic skin wound healing.

2. MiRNAs in Diabetes Complications

The extraordinary discovery of miRNAs by Ambros and co-workers, in 1993, gave new insights into the regulation of the genome, and further findings in recent years have impacted our understanding of gene regulation at the post-transcriptional level [23]. They are a novel class of non-coding RNAs that are expressed in all tissues and play major roles in human diseases, including diabetes [19,20,21]. More importantly, these miRNAs can also be found in the circulation, thus being available as biomarkers for monitoring of disease onset and progression. Moreover, the circulating miRNAs are reflective of those in the tissues. As a result, they have great potential as accurate diagnostic and prognostic markers, as well as being viable therapeutic targets for treating diabetes complications. Not only do miRNAs inhibit translation by binding to the 3' untranslated region (3'UTR) of their target mRNA [24], they can also trigger gene activation [25,26]. There is an emerging interest in these small, evolutionarily conserved regulatory markers, the non-coding RNAs and their involvement in health and disease, and there is already strong evidence for their important roles in the developmental modulation of growth control, tissue architecture, signaling pathways and disease pathology regulation. However, in spite of the many miRNA studies performed thus far, their organization within the genome, as well as their regulatory biology, remain to be well defined. A large number of miRNAs has already been discovered and described in relation to their vast targets, and of these, a number of specific miRNAs have appeared as major regulators of particular aspects of disease pathologies including diabetes complications. A great deal of attention has recently been given to the role of miRNAs and the different diabetes complications. Therefore, this review will focus on the relevance of miRNAs in the macrovascular and microvascular defects in diabetes, with particular emphasis on the different phases of diabetic skin wound healing.

2.1. Macrovascular Complications

2.1.1. Cardiomyopathy

Diabetes is an independent risk factor and a major cause of chronic cardiovascular complications, some of which affect the vasculature, leading in particular to coronary arterial disease, stroke, hypertension, atherosclerosis and ultimately to heart failure, characterized by the presence of molecular, structural and functional changes [27,28]. Cardiomyopathy, a weakening of the heart muscle, is the measurable deterioration of the function of the myocardium. About 80% of deaths associated with diabetes are due to heart disease [29,30,31]. It is of paramount importance to identify early biomarkers to be able to diagnose the disease while in its early stages and through this alter the prognosis. Development of novel interventions for therapy is also needed. Several studies have focused on identifying miRNAs, as diagnostic and therapeutic tools involved in the symptoms and development of diabetic cardiovascular complications. Several reviews have recently been published summarizing important findings, regarding the putative mechanisms of the disease in relation to the miRNAs involved for use as potential diagnostic markers, as well as therapeutic targets [29,32,33,34,35,36,37,38,39]. One study identified four miRNAs in circulation, comprising miR-1, miR-16, miR-26a, and miR-133a, the latter, a possible biomarker that can help distinguish Takotsubo cardiomyopathy from ST-segment elevation acute myocardial infarction [40]. These pathologies have until now been clinically indistinguishable. Furthermore, the downregulation of miR-548 family members (miR-548c and -548i), was identified through genome-wide miRNA-microarray using peripheral blood mononuclear cells, which are more easily available than heart tissue samples [41]. This suggested that these markers could be used to detect early heart failure [41]. Moreover, miR-22, expressed in cardiac and skeletal muscle, was found upregulated during myocyte differentiation and cardiomyocyte hypertrophy, and it has been suggested as a regulator of cardiomyocyte hypertrophy and cardiac remodeling, with Sirt1 and Hdac4 as its targets [42]. Left ventricular hypertrophy is a compensatory mechanism in response to cardiac stress leading to heart failure. Recently, a study found that cardiac fibroblasts secrete miRNA-enriched exosomes. They identified miR-21-3p (miR-21), derived from fibroblast exosomes, as a potent paracrine-acting RNA molecule that induces cardiomyocyte hypertrophy [43]. In addition, pharmacological inhibition of this biomarker could lead to attenuation of the pathology [43].

2.1.2. Atherosclerosis

Hypertension and hyperlipidemia significantly contribute to the formation and progress of the atherosclerotic plaque [44,45]. In addition, both endothelial dysfunction, induced by high circulating glucose and lipid levels, and inflammation mostly provoked by immune responses mediated by macrophages and T-cells, has been implicated in the pathogenesis of atherosclerosis and vascular disease [46,47]. These processes are highly regulated by miRNAs and specific miRNAs have now been shown to play crucial roles in regulating lipid metabolism [48] and inflammation [47]. Several reviews have documented this topic, from oxidative stress [49,50] inflammation [51,52] and the development of atherosclerotic plaque [53]. The use of miRNAs as biomarkers for atherosclerosis diagnosis and prognosis [54,55] and their relation to aging [56] has been reviewed recently. Furthermore, miR-155 has recently been implicated with atherosclerosis, as a modulator of actin cytoskeleton organization in endothelial cells, through alterations in the small GTPase RhoA and myosin light chain kinase [57]. In addition, inhibition of miR-155 with antagomiR-155 can decrease lipid-loading in macrophages and reduce atherosclerotic plaques [58]. MiR-144-3p has also been implicated as essential for the regulation of both cholesterol homeostasis and inflammatory reactions [59]. Furthermore, miR-21 has been identified as having a protective role in cardiomyocyte apoptosis induced by ischemia-reperfusion and hypoxia-reperfusion, dependent on the phosphatase and tensin homolog (PTEN) and the serine/threonine-specific protein kinase AKT/PKB pathway [60]. Platelets play an important role in atherosclerosis and platelet-released miR-223 working via the insulin-like growth factor (IGF)-1 receptor can promote vascular endothelial cell (VEC) apoptosis induced by advanced glycation end products (AGE) [61]. This indicates that platelets can modulate VEC apoptosis through the release of miR-223. In addition, the nuclear receptor, liver X receptor (LXR) signaling in macrophages can modulate cholesterol homeostasis and the inflammatory response, pathways involved in atherosclerosis. Moreover, recent work identified miR-206 as a putative regulator of LXRα in macrophages, with inflammatory stimuli greatly inducing miR-206 expression [62]. Resistin, an insulin resistance biomarker, seems to be a key factor in atherosclerosis and as reported recently high glucose stress was able to induce a significant decrease in miR-492 expression, with a consequent upregulation of resistin expression [63]. On the other hand, upregulation of miR-492 attenuated endothelial cell migration and lipid accumulation.

2.2. Microvascular Complications

2.2.1. Diabetic Retinopathy

Diabetic retinopathy is one of their leading causes of blindness [64]. It affects up to 80% of all patients who have had diabetes for 10 years or more [65,66]. Risk factors for progression of diabetic retinopathy are hyperglycemia, hypertension, hyperlipidemia, and smoking [65,66]. Hyperglycemia, insulin signaling abnormalities and inflammation lead to retinal microvascular defects, neuroretinal dysfunction and degeneration [32,38,67]. Major symptoms include pericyte death and thickening of the basement membrane, leading to weak vascular walls. miRNAs play an important role in the mechanisms underlying the pathogenesis of retinopathy [38,68]. A summary of the important miRNAs for retinopathy is presented in Table 1. One of the first studies demonstrating the importance of miRNAs in diabetic retinopathy carried out a large miRNA-expression profiling assay on the retina and retinal endothelial cells of streptozotocin-induced diabetic rats [69]. Kovacs and colleagues found several miRNA signatures for the upregulation of the transcription factor nuclear factor (NF)-kB, vascular endothelial growth factor (VEGF), and p53, reflecting the pathologic alterations of retinopathy [69]. Moreover, they found that, in particular, miR-146 is a potential therapeutic target through its inhibition of NF-kB activation in retinal endothelial cells [69]. They also indicated that the miR-34 family is upregulated in diabetic rats and some of them are important markers in the retina. Another study indicated the involvement of miR-34a in the proliferation and migration of retinal pigment epithelial (RPE) cells, important in vitreoretinopathy [70]. In addition, apoptosis of retinal neurons is one of the important players in diabetic retinopathy [71,72]. Studies in streptozotocin diabetic rats have suggested that miR-29b may have a protective role against the apoptosis of retinal ganglion cells and cells of the inner nuclear layer of retinas [73]. Another group, using microarray screening assays, found that 304 miRNAs were differentially expressed in the transforming growth factor (TGF)-β2-induced epithelial-mesenchymal transition of human retinal pigment epithelium cells [74]. An important finding because this event is imperative during the development of proliferative vitreoretinopathy. Moreover, not only can TGF-β2 mediate fibrosis but it can also induce cell migration [75] and therefore it would be important to identify the targets for these miRNAs. One of the key mechanisms causing retinal microvascular injury in diabetes is endothelial cell damage. Recent results have identified a novel mechanism by which miR-195 regulates sirtuin (SIRT)-1 mediated tissue damage in diabetic retinopathy. The expression of miR-195 was found to be upregulated in retinas of diabetic rats while intravitreal injection of antagomiR-195 ameliorated levels of SIRT-1 [76]. Hyperglycemia has been suggested as the cause for high miR-195 expression levels found [76]. Furthermore, hypoxia-inducible factor 1 alpha (HIF1α) and VEGF are both implicated in the pathogenesis of diabetic retinopathy [77]. Ling and colleagues recently found that there is a cross-talk between HIF1α and VEGF through the expression of common miRNAs, such as miR-106a, and that silencing either HIF1α or VEGF increased the availabilities of the shared miRNAs [78]. In addition, it has been shown that miR-126 is not only downregulated under hypoxic conditions in vivo and in vitro, but it can also modulate the expression of VEGF and MMP-9 protein levels in monkey chorioretinal vessel endothelial cells (RF/6A) [79]. Moreover, miR-200b has been involved in the regulation of oxidation resistance (Oxr)-1, a protein that controls the sensitivity of neuronal cells to oxidative stress, in the retinas of Akita mice, a model of type 1 diabetes, where it appears to be upregulated [80], while in another study the same miRNA has been found downregulated upon high glycemia in diabetic retinas and endothelial cells, having VEGF as a possible target [81]. These findings could be very significant from a therapeutic perspective, since miRNAs are important in neovascularization, matrix protein accumulation and vascular permeability, all important contributors for loss of vision. Much more work in vivo needs to be done in order to identify and validate the specific targets and pathways that can be modulated by some of these differentially expressed biomarkers.
Table
Table 1. Summary of miRNAs that are involved in diabetic retinopathy.
Table 1. Summary of miRNAs that are involved in diabetic retinopathy.
microRNAsDiabetic Retinopathy—miRNA Functions
miR-132, miR-155, miR-146, miR-21Upregulated with increased NF-kB, ICAM-1 and MCP-1, in diabetic retinal endothelial cells and retinas [69].
miR-34 familyUpregulated in diabetic rats upon VEGF and p53 responses, including in retinas [69].
miR-34aDownregulated in subconfluent retinal pigment epithelial cells. It can inhibit their proliferation and migration [70].
miR-29bUpregulation at the early stages of diabetes with potential target the cellular activator of x cellular activator of PKR, RAX (PKR activator X), in retinal ganglion cells [73].
miR-195Upregulated in retinas of diabetic rats. Regulates sirtuin 1 mediated tissue damage, in human retinal and dermal microvascular endothelial cells [76].
miR-195Upregulated in retinas of diabetic rats. Regulates sirtuin 1 mediated tissue damage, in human retinal and dermal microvascular endothelial cells [76].
miR-200bDownregulated upon high glycemia with VEGF as a direct target, in diabetic retinas and endothelial cells [81].
Upregulated in Akita mouse retinas. Regulates the expression of oxidation resistance-1 [80].
miR-126Downregulated by hypoxia and reduced in the retinal tissue of streptozotocin-induced diabetic rats. VEGF and MMP-9 are possible targets [79].
NF-kB, Nuclear factor kappa-light-chain-enhancer of activated B cells; ICAM-1, Intercellular adhesion molecule 1; MCP-1, Monocyte chemoattractant protein-1; VEGF, Vascular endothelial growth factor; RAX, PKR activator X; HIF1α, Hypoxia-inducible factor 1-alpha; Oxr-1, Oxidation resistance-1; MMP-9, Matrix metallopeptidase 9.

2.2.2. Diabetic Nephropathy

Diabetic nephropathy, occurs in about 50% of the patients with T2DM, resulting in chronic kidney disease and organ failure [82,83]. It is the leading cause of progressive kidney disease and it contributes to the increased morbidity and mortality among individuals with diabetes [84,85]. Both high blood pressure and high levels of blood glucose increase the risk for nephropathy. Moreover, as kidney filtration starts to fail, various proteins start leaking into the urine causing proteinuria, and wastes, such as uric acid, accumulate in the blood. As a consequence osmolality increases and blood pressure climbs, enhancing kidney failure [86,87]. Chronic inflammation [88,89] and oxidative stress [90,91] also contribute to this pathology [32]. One of the most important players in the progression of renal diseases is TGF-β. However, additional downstream targets and pathways remain to be identified [92,93]. miRNAs have been identified as regulating their own gene expression, as well as influence entire signaling networks [19]. Much work has been dedicated into trying to understand how miRNAs regulate and are regulated by factors that contribute to kidney disease [32,33,94]. Nephropathy is one of the research areas where most miRNA dysregulations have been identified. Recent reviews have analyzed the effects of miRNAs, on diabetic nephropathy, from normal kidney function [95,96], to kidney fibrosis [97], glomerular podocyte dysfunction [98], blood pressure regulation [99], the renin-angiotensin system, advanced glycation end products (AGE)/RAGE (receptor of AGEs) signaling under oxidative stress [100] and kidney inflammation [32]. Most recently, the TGF-β signaling pathway has been implicated with upregulating miR-21 and miR-192, whereas downregulating miR-29 and miR-200, important in renal fibrosis [101]. Mesangial proliferation and glomerular hypertrophy are abnormalities in nephropathy. Results have indicated that down-regulation of miR-34a can inhibit mouse mesangial cell proliferation and, therefore, alleviate glomerular hypertrophy in vivo [102]. In addition, regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 could contribute to podocyte homeostasis and renal function [103]. The study demonstrated that overexpression of miR-29a attenuated HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion, associated with diabetes and restored nephrin acetylation, demonstrating a possible protective effect of miR-29a against diabetic kidneys. Moreover, the use of miRNAs as biomarkers for nephropathy, both diagnosis and follow-up [67,85] and as potential therapeutic targets [104], has been further reviewed elsewhere.

2.2.3. Diabetic Neuropathy

Diabetic neuropathy is nerve damage occurring in the presence of diabetes, with prevalence greater than 50% in patients with long-standing disease [105,106,107]. There are sensorimotor and autonomic neuropathies. Sensorimotor neuropathy may include pain, paraesthesia and sensory loss [108,109], while autonomic neuropathy may contribute to myocardial infarction, malignant arrhythmia and sudden death [110]. It is chronic hyperglycemia and associated metabolic defects (mainly oxidative stress, vascular damage and ischemia) that can lead to injury of nerve fibers throughout the body [32,109,111,112]. Sensory neurons are responsible for diabetic peripheral neuropathy, often resulting in pain or numbness in hands and feet [108,109]. Neuropeptide expression and respective signaling pathways, responsible for inducing pro- or anti-inflammatory cytokine expression, are highly involved in diabetic wound healing. However, they are compromised in the neuropathic state, as neuropeptide release through the C-nociceptive fibers is impaired [13,113,114,115]. Unlike for nephropathy and heart disease, little is known about the role of miRNA in neuropathic complications. However, a recent study using genome wide studies and miRNA sequencing was able to identify three miRNAs that were differentially regulated in neuropathy: miR-30d-5p and miR-125b-5p, two major players in regulating the expression of TNF-α, brain-derived neurotrophic factor (BDNF) and signal transducer and activator of transcription (STAT)-3, as well as miR-379-5p, all closely associated with neuropathic pain [116]. Furthermore, miR-203, miR-96 and miR-7a have also been identified as regulators of protein expression in the dorsal root ganglion, also associated with neuropathic pain [117,118,119]. In addition, polymorphisms have been identified in miR-128a and miR-146a, with susceptibility for diabetic polyneuropathy, and in miR-146a and miR-27a, with susceptibility for cardiovascular autonomic neuropathy [120]. Regarding nerve repair, in particular Schwann cell migration, a recent study identified miR-9 as an important regulator [121]. Even though, potential miRNAs have been identified as regulators of some particular neuropathies, much remains to be done in order to further validate their role in the mechanisms underlying these neuropathies.

3. MiRNA in Diabetic Wound-Healing Impairment

One of the major causes of diabetes-associated morbidity and mortality is lower limb amputation, which is a consequence of DFU [3,13]. In contrast to acute wounds that progress through the phases of wound healing linearly in healthy individuals, chronic wounds in diabetic patients become stalled in different phases and progression does not occur in synchrony due to diabetes associated neuropathy, microangiopathy and impaired immune function [122]. Recent studies have demonstrated the importance of miRNAs in the regulation of gene expression in various cells of the skin, including stem cells, immune cells and keratinocytes. In mesenchymal stem cells (MSCs), miR-27b was identified as a unique signature of the stem cell niche in burned mouse skin, suppressing the migration of mMSCs by targeting stromal cell-derived factor (SDF)-1D [123]. In addition, miR-27b was shown to rescue impaired bone marrow-derived angiogenic cell angiogenesis via thrombospondin (TSP)-1 suppression [124]. It has been shown that keratinocytes recognize invading pathogens by various receptors, among them Toll-like receptors (TLRs). Recent results show that Toll-like receptors may be able to alter the miRNA expression profile of keratinocytes, including miR-146a [125]. This could implicate the role of miRNAs in modulating the innate immune response of these cells. Some of these studies have been extensively reviewed [126,127], therefore, we will focus our attention on the important roles of miRNAs in the different phases of wound healing, as summarized in Figure 1.
Genes 05 00926 g001 1024
Figure 1. Schematic representation of the different wound healing phases and a summary of the most relevant miRNAs thus far identified, that are involved in wound healing impairment in diabetes. Arrows indicate wound up- or downregulation.
Figure 1. Schematic representation of the different wound healing phases and a summary of the most relevant miRNAs thus far identified, that are involved in wound healing impairment in diabetes. Arrows indicate wound up- or downregulation.
Genes 05 00926 g001

3.1. Inflammatory Phase

Immediately after the skin barrier is breached, coagulation is triggered and usually homeostasis is achieved within minutes. Independently of the extent of the wound, before tissue integrity is restored, pathogens can infect the exposed tissues underlying the damaged skin. This is when the inflammatory phase of wound healing begins (Figure 1). During this period the immune system identifies and eliminates the infecting pathogens and damaged cells. To do so, the various immune cells travel to the wound site and interact with the various skin cells, in an orchestrated orderly fashion [128,129,130]. Selective leukocyte homing to the wound site is controlled either by the inflamed tissue, through the regulation of chemokine gradients [131] or by the infectious agents themselves, mainly by N-formil-methionine peptides, with bacterial origin [132], making the immune response proportional to the wound area. We are now starting to unravel how miRNAs are involved in the regulation of both chemokine and chemokine receptor gene expression.
Zhai and others revealed that the expression of important inflammatory chemokines, like chemokine (C-C motif) ligand (CCL)2, important for monocyte, basophil, dendritic cell and Th2 T-cell chemotaxis, is controlled by miRNAs [133]. Nakamachi and others later identified miR-124a as responsible for the diminished CCL2 mRNA stability and decreased CCL2 expression in fibroblast-like synoviocytes from patients [134]. Dorhoi and others concluded that miR-223 directly targets chemokine (C-X-C motif) ligand (CXCL)2 and CCL3, both important for neutrophil recruitment to the wound site [135]. This data is of particular importance for the understanding of the diabetic wound healing impairment, since, in a diabetic rabbit model, both CXCR1 and CXCR2, the receptor for CXCL2, were found to be under-expressed in endothelial cells, surrounding the wound, when compared to controls [136]. Moreover, IL-8, the ligand for CXCR1, was also found to be under-expressed in endothelial cells from DFUs [137], and its expression is regulated by miR-155 (upregulated) [138] and miR-93 (downregulated) [139]. It is not clear yet if any of these miRNAs are involved in modulating the DFU pathology.
Leukocyte retention is also important for the destruction of affected cells and tissue repair [140]. Harris and others [141] have demonstrated that miR-126 decreases leukocyte adherence to endothelial cells, and Ortega and others [142] have demonstrated that it regulates vascular cell adhesion molecule (VCAM)-1 expression. T2DM patients have decreased levels of this particular miRNA [143]. Moreover, the expression of CD38, a glycoprotein necessary for immune cell adherence to human vein endothelial cells [144], is downregulated by miR-140-3p, that specifically binds to CD38 3'-UTR [145]. T2DM patients also have increased levels of miR-140-3p [146], but there is no data on CD38 activation and expression in these patients.
Inflammation is also directly or indirectly controlled by miRNAs. Figure 1 indicates some of the miRNAs involved in this process in regard to wound healing. miR-16 has been shown to inhibit cyclooxygenase (COX)-2 (also known as prostaglandin-endoperoxide synthase 2) expression [147], demonstrating a systemic anti-inflammatory effect. COX-2 is overexpressed in T2DM patients [148], but it is not yet clear if this effect is due to miR-16 modulation. Nevertheless, it is known that there is a link between miR-16 and obesity [149], one of the major pathologies leading to T2DM. Interestingly, in humans, surgery-induced weight loss led to a decrease in miR-16 levels, but the same was not true for diet-induced weight loss [150]. On the other hand, miR-203, usually associated with β-cell apoptosis in type 1 diabetes mellitus (T1DM) [151], is also responsible for the inhibition of TNF-α and IL-24 expression in the skin [152]. Since increased TNF-α levels favor DFU formation [153], the overexpression of miR-203 should give some degree of protection from DFU formation to these patients. Since DFU formation usually occurs many years after β-cell depletion, it would be important to know if miR-203 levels stay high after β-cell depletion, conferring protection from DFU or if miR-203 levels decrease.
After the pathogen burden has been eliminated, inflammation has to be terminated, in order for the healing to continue [109]. This is one of the most important steps where diabetic wound healing fails [153]. In fact, one of the common denominators for all chronic wounds is the persistent inflammatory state [154]. One particular miRNA, that plays a key role as a molecular brake on inflammation, miR-146a, is significantly downregulated in diabetic mouse wounds [155]. Although DFU patients are unable to mount an acute and sufficient immune response to wound infecting bacteria, they present a systemic pro-inflammatory environment, with elevated IL-1, TNF-α, IL-6 and regulated on activation, normal T-cell expressed, and secreted (RANTES) levels [88]. Hyperglycemia alone is able to activate the transcription factor NF-kB [156], impairing leukocyte activation [157] and migration [158]. It is reasonable to speculate that the downregulation of miR-146a is linked to, or even responsible for all these effects, as proposed by Balasubramanyam and others [159]. Their results have demonstrated an inverse correlation between miR-146a expression and glycated hemoglobin, insulin resistance, tumor necrosis factor receptor-associated factor (TRAF)-6, and NF-kB mRNA levels and circulatory levels of TNF-α and IL-6.

3.2. Proliferation Phase

Cytokines and chemokines released by inflammatory cells eventually attract fibroblasts and myofibroblasts to the injury site, initiating the proliferation phase, characterized by the formation of granulation tissue and deposition of collagen and glycosaminoglycans [160]. In fact, cytokines control the expression of various miRNAs in fibroblasts [161]. One such miRNA is miR-155, of which transfection, in a mouse model of lung fibrosis, increased fibroblast migration and, consequently, lung fibrosis [161]. A recent study [162] has shown that miR-155 expression is significantly decreased in blood mononuclear cells from T2DM patients. The expression of miR-155 is also decreased in diabetic mice and its over-expression is able to prevent cardiac fibrosis in these mice [163]. Madhyastha and others [164] have analyzed the miRNA signature in diabetic wound healing and identified 14 miRNAs that were differentially expressed in diabetic skin, among these, miR-21 showed increased expression in diabetic skin, but decreased expression during diabetic wound healing (Figure 1). They also demonstrated that reduced miR-21 expression in diabetic wounds decreases the rate of fibroblast migration [164].
With the onset of the proliferation phase new blood vessels are created to supply the area undergoing regeneration with nutrients and oxygen, and extracellular matrix (ECM) is synthesized in order to rebuild the damaged tissue. During this phase the injured dermis starts getting red (erythema) and gain volume (edema) [165]. As macrophages and other cells produce and release VEGF, they play a direct role in neovascularization and angiogenesis [166]. Various miRNAs involved in the regulation of angiogenesis appear to be dysregulated in diabetic patients [167]. miR-27b is downregulated in endothelial progenitor cells (EPCs) from T2DM patients [168]. In diabetic mice, its overexpression rescued impaired bone-marrow derived angiogenic cell function via TSP-1 suppression, and topic miR-27b delivery improved diabetic mouse skin wound closure [164]. In a rat model, miR-328 has been shown to inhibit the formation of capillary structures by targeting CD44 expression [169], and others have shown that miR-328 is overexpressed in diabetic individuals [170]. miR-503 has also been shown to impair angiogenesis and its expression is upregulated in T2DM patients [171]. Furthermore, the miR-143/145 cluster has been implicated in insulin resistance and the development of T2DM [172,173] and has also been demonstrated to inhibit angiotensin II formation [174], by targeting angiotensin-converting enzyme (ACE) thus, impairing wound healing (Figure 1). On the other hand, ACE inhibitors have been shown to reduce all-cause mortality in diabetic patients [30], leading us to conclude that the miR-143/145 cluster may also have a systemic protection effect in diabetic patients. Moreover, miR-126 also promotes endothelial cell proliferation, migration and angiogenesis [175,176] and is significantly reduced in susceptible individuals and T2DM patients [143]. Aberrant expression of miR-16, miR-20a, miR-21, miR-106a, miR-130a and miR-203, have been found in venous ulcers studies [177]. These miRNAs have been predicted to target multiple genes important for wound healing, like early growth response factor 3, vinculin and the leptin receptor [177].
The migration, proliferation and differentiation of keratinocytes are, altogether, a key step in wound healing because hair follicle keratinocytes (first) and epidermal keratinocytes (later) will eventually fill in the gap created by the wound and restore the integrity of the skin. Various miRNAs, such as miR-198, miR-203 and miR-483-3p, are known to inhibit keratinocyte migration and proliferation [178,179,180]. All these miRNAs are downregulated in normal skin wounds, whereas the expression of miR-198 persists in diabetic wounds [178], and the expression of both miR-203 and miR-483-3p is upregulated in diabetic mice [151,181]. On the other hand, miR-95, miR-203 and miR-210 promote keratinocyte differentiation [182] and both miR-203 and miR-210 are upregulated in diabetic mice [151] and miR-210 is upregulated in both T1DM [183] and T2DM [184] patients. Moreover, miR-21 has a variety of effects on wound healing, one of which is to promote keratinocyte migration and re-epithelialization [185,186]. The expression of miR-21 is usually increased in diabetic patients, because it is overexpressed in response to high glucose levels [187], but is decreased in diabetic wounds, when compared to normal wounds [164]. The expression of miR-21 must be tightly controlled in skin wounds because despite its beneficial effect on wound healing, its overexpression inhibited epithelialization and granulation tissue formation in a rat wound model [177]. It has also been demonstrated that the miR-99 family members, overexpressed in diabetic patients [188], reduce re-epithelialization of dermal wounds by targeting the AKT/PKB/mTOR signaling pathway [189]. Furthermore, the miR-200 family of miRNAs appears to controls epithelial to mesenchymal transition (EMT) [190], an essential phenomenon for wound re-epithelialization to occur, and is dysregulated in diabetic mice [191].

3.3. Maturation Phase

The maturation phase can last several weeks and occurs once the wound has closed (Figure 1). It is characterized by ECM adjustment, remodeling of collagen from type III to type I, and the replacement of granulation tissue by scar tissue [3]. Cellular activity decreases and the number of blood vessels in the wound decrease [192]. Results indicate that mRNA expression for α1-procollagen was reduced in diabetic wounds in a diabetic mouse model, resulting in increased matrix rigidity [193]. In the same study reduced alpha-smooth muscle actin (α-SMA) staining in the cells and lack of orientation of fibroblasts in diabetic skin, was observed [193], which could affect the efficient contraction of the wound [194]. Interestingly, miR-196a expression is down-regulated by TGF-β that, in turn, is increased in diabetes [195]. Moreover, miR-196a has been shown to down-regulate the expression of type I and III collagens in fibroblasts [196], improving wound healing in a keloid fibroblast model. Recent studies have also demonstrated that miR-196a inhibits the expression of the homeotic gene Hoxc8, a repressor of brown adipogenesis [197]. They have shown that forced expression of miR-196a in mouse adipose tissue increases energy expenditure, thereby rendering the animals resistant to obesity and diabetes. These observations suggest that the overexpression of miR-196a in diabetic patients may also improve wound healing.
Activin A has an important impact in the maturation phase of wound healing, as it promotes the replacement of fatty tissue by connective tissue [198], as well as, re-epithelialization and granulation tissue formation [199]. The high levels of activin A, observed in blood of T2DM patients [200] inhibits insulin action in cardiomyocytes via the induction of miR-143, which in turn, suppresses the novel regulator of insulin action, the oxysterol-binding protein-related protein 8 [173]. On the other hand, the expression of miR-210 is enhanced by high glucose in endothelial cells cultured in vitro [184]. It has also been found upregulated in diabetic mice [151] and diabetic patients [183,184], silencing activin A receptor type 1B [201], possibly compensating the effect of the high activin A levels. miR-29b has been demonstrated to directly target ECM genes, such as fibronectin, collagen type I, and collagen type III [202,203]. The in vivo topical application of miR-29b to mouse wounds improved collagen type III/I ratios and generated a significantly higher matrix metalloproteinase 8 activity, enhancing scarless wound healing [204]. As stated above, repairing a defect in the human skin is a highly orchestrated physiological process involving numerous factors that act in synergy to re-establish barrier function by regenerating new skin. It has been shown by several studies that miRNAs are very important markers and modulators of the different phases of wound healing [205,206,207]. In this section we have analyzed the involvement of miRNAs in the dysregulation of diabetic wound healing and summarized the phases of wound healing and the miRNAs involved in DFU in Figure 1 and Table 2.
Table
Table 2. Summary of the most relevant miRNAs involved in the different phases of wound healing.
Table 2. Summary of the most relevant miRNAs involved in the different phases of wound healing.
Phases of Wound HealingmiRNA InvolvedFunctions
InflammationmiR-16Inhibits COX-2 expression in monocytes [147].
miR-126Decreases leukocyte adherence to endothelial cells [141].
miR-146aKey role as a molecular brake on inflammation [155].
miR-203Inhibits TNF-α and IL24 expression [152].
ProliferationmiR-21Promotes keratinocyte migration and re-epithelialization [185,186], increases the rate of fibroblasts migration towards the wound [164] and delays epithelialization [177].
miR-27bRescues impaired BMAC angiogenesis via TSP-1 suppression [124].
miR-99 familyReduces re-epithelialization of dermal wounds [189].
mir-126Promotes endothelial cell proliferation, migration and angiogenesis [175,176].
miR-143/145Inhibits angiotensin II formation [174].
miR-155Inhibits KGF expression in fibroblasts [161].
miR-198Inhibits keratinocyte migration [178].
miR-200 familyControls epithelial-mesenchymal transition [190].
miR-203Inhibits keratinocyte proliferation and migration [180] but promotes keratinocyte differentiation [182].
miR-210Promotes keratinocyte differentiation [182] and silences Activin A receptor type 1B [201].
miR-328Inhibits the formation of capillary structures [169].
miR-483-3pInhibits keratinocyte proliferation and migration [179].
miR-503Impairs angiogenesis [171].
MaturationmiR-29bIn vivo topical application to mouse wounds improves collagen type III/I ratios and generates a higher matrix metalloproteinase 8 activity [204].
miR-143Inhibits insulin action in cardiomyocytes from T2DM patients [200].
miR-196aDecreases expression of type I and III collagens in fibroblasts [196] and its overexpression renders mice resistant to obesity and diabetes.
miR-210Silences activin A receptor type 1B [201].
COX-2, cyclooxygenase-2; TNF-α, Tumor necrosis factor α; IL24, Interleukin 24; BMAC, bone marrow-derived angiogenic cell; TSP-1, thrombospondin-1; KGF, KGF expression in fibroblasts.

4. Potential of MiRNAs as Early Biomarkers for Detection and Treatment of Diabetic Foot Ulceration

The ideal biomarker for any disease would be a molecule that would be produced in the earliest stages of a particular disease and that would not be produced, at least in the same quantities, in any other condition. Such molecule should be easily collected by non-evasive means, preferably from the blood or urine, and would be stable enough to be quantified in conventional clinical laboratories. Although this perfect biomarker is still elusive, in the case of diabetes and its complications, the conventional biomarkers are either not specific, such as cholesterol, creatinine, free fatty acids, lipoproteins, c-reactive protein or adipokines, or not able to identify the early stages of the disease, like hyperglycemia, insulin, glutamate decarboxylase, islet-cell dysfunction and auto-antibodies in the case of T1DM, tyrosine phosphatases or incretin levels. Moreover, we are still not able to easily identify individuals at risk of developing diabetes mellitus and its associated complications. Ideally, a biomarker should also change in form or quantity with disease progression or/and with a therapeutic intervention. None of the referred biomarkers or any other currently used by clinicians meets all or even most of the referred specifications. This is why miRNAs hold a promising potential. miRNAs are easily collected and stable enough to be analyzed in a clinical environment, possibly using automated methods [208,209,210,211]. The use of miRNAs as biomarkers for the various types of diabetes, as well as their macrovascular and microvascular complications has been recently and extendedly reviewed [36,67,94,212,213,214] and will not be discussed here. Instead, we will focus on the use of miRNAs as biomarkers and therapeutic targets for the diabetic wound healing complications.

4.1. MiRNAs as Biomarkers for the Development of Chronic Diabetic Ulceration

The idea of using miRNAs as biomarkers for diabetes and its complications has come from studies using large cohorts of patients, usually using microarray profiling, later confirmed by qPCR, where several miRNAs have been identified as being dysregulated in the blood, either whole blood or its fractions, from diabetic patients. These studies have even allowed for the discrimination of a specific miRNA profile for T1DM [183,215,216] and T2DM [142,217]. Despite the large amount of data collected, no specific miRNA has been identified as being a biomarker for diabetic wound healing impairment. Nevertheless, the accumulating data on miRNA dysregulation in DFU, here reviewed, allows us to predict good candidates to be tested as possible DFU biomarkers (Figure 1 and Table 2).
The reduced expression of miR-21 in diabetic wounds [164] and the multitude of its functions exerted in wound healing [186] makes it a good candidate as a DFU biomarker. miR-21 is involved in the various phases of wound healing, especially in the control of keratinocyte and fibroblast migration to the wound site [164,185]. The reduced expression of miR-21 is able, by itself, to significantly delay wound re-epithelization [177].
Another good candidate would be miR-126. Its expression is significantly reduced in susceptible individuals and T2DM patients. miR-126 is involved in leukocyte migration to the wound site [141,142], endothelial cell proliferation, migration and angiogenesis [175,176]. The fact that miR-126 is decreased in individuals susceptible for diabetes [143], and the lack of evidence indicating that it is decreased in other non-related pathologies, makes it a promising marker for early diabetes detection.
Both miR-203 and miR-210 are also good biomarker candidates because of their increased expression in diabetic mouse models [151] and in both T1DM and T2DM [183,184]. These miRNAs have been predicted to target multiple genes important for wound healing [177]. miR-203 is associated with β-cell apoptosis [151] and it also inhibits the expression of TNF-α and IL-24 in the skin [152]. In addition, it inhibits keratinocyte migration and proliferation [178,179,180], but promotes keratinocyte differentiation [182]. miR-203 has also been associated with neuropathic pain [117,118,119]. On the other hand, miR-210, whose expression is enhanced by hypoxia and high glucose levels [184], silences activin A receptor type 1B [201] and, similarly to miR-203, it also promotes keratinocyte differentiation [182].

4.2. MiRNAs as Therapeutic Targets for Chronic Diabetic Ulceration

Due to our lack of understanding on why wound healing is impaired in diabetes, the approach to DFU healing has relied on lower limb amputation or it is mainly addressed at the prevention level [218]. The therapeutic approach has been limited to the administration of growth factors [219] and, more recently, tissue reconstruction using endothelial progenitor cells [220], or stem cells [221], with limited results. miRNA-based therapy strategies show great potential, aided by the increasing rise of nanotechnology, with promising results and few side-effects [222].
The selective knockout of specific miRNAs, either by gene manipulation or by the use of antagomiRs has proven successful, both in vitro and in vivo [223,224]. Several miRNAs enhanced in diabetes or its complications have been targeted with relative success in diabetic mouse models, while others have been proposed as potential therapeutic targets [197]. miRNAs targeted with success in other pathologies or normal conditions may also prove useful in diabetes. For example, van Solingen and others have proven that miR-155 knockout mice display improved repair of dermal wounds [225]. Although the expression of miR-155 is not enhanced in diabetic patients, since it plays an important role in inflammation, it may be a tentative target to reduce the enhanced inflammation observed in DFU patients.
The replenishment of miRNAs is much more difficult due to several limitations, such as in vivo delivery methods and tissue specificity. However, once these limitations are overcome, they could also become a novel therapeutic strategy [119]. One other limitation for the use of miRNAs as therapeutic targets is their usually high redundancy. As an example, Kovacs and others [69] have proposed that miR-146 could be a good therapeutic target in diabetes, due to its role as a molecular brake on inflammation [159] and the fact that it is significantly downregulated in diabetic mouse wounds [155]. However, the upregulation of miR-146 in a mouse model, not only did it not downregulate several pro-inflammatory markers (IRAK-1 and TRAF-6) and cytokines (TNF-α, IL-6 and IL-1β) [226] but it also generated autoimmune disorders mimicking the human autoimmune lymphoproliferative syndrome [227]. In this case, the treatment with mesenchymal stem cells proved to be more efficient, because it not only upregulate miR-146a expression, but it also enhanced wound healing in diabetic mice [155].
Due to these difficulties, the use of miRNAs as therapeutic targets for DFU remains an open challenge and every diagnostic biomarker should be considered as a possible therapeutic target. For instance, the upregulation of both miR-21 and miR-126 should enhance wound healing by stimulating leukocyte migration to the wound site, promoting bacterial control and wound closure, through the enhancement of keratinocyte and fibroblast activation and migration and improved angiogenesis. The downregulation of miR-203 and miR-210 should also enhance wound healing by promoting keratinocyte migration and proliferation.

5. Conclusions

MiRNAs are a fascinating area of RNA biology due to their roles in the fine-tuning of many physiological processes, and their modulation in human diseases. miRNAs are regulatory molecules that contribute to numerous aspects and phases of diabetes and its complications, including the impaired wound healing observed in DFU. They can play diverse roles as activating specific signaling pathways, upregulating or downregulating the expression of certain genes, depending on the stimuli. It has become clear that some of these molecules may provide valuable information within a clinical setting, potentially acting as screening tools for high-risk patients, becoming early predictive diagnostic tools, while informing the treatment decision-making process. Many of the results obtained so far on several of these miRNAs, have been the result of large screening studies, or have been performed in in vitro cell systems. Therefore, many of these markers still need to be validated in in vivo settings, where the promiscuity and diversity of interactions may pose some serious problems and invalidate clinical applications. Most importantly, we do not yet understand how many of these miRNAs exert their functions, either because we lack critical knowledge of the pathways involved, or because we are only seeing a small fraction of the “big picture”, since most of these miRNAs exert different functions according to the tissues and conditions where they are expressed. Nevertheless, once validated in vivo, they may themselves be considered direct therapeutic targets.

Acknowledgements

This work was financed by FEDER funds by the operational program Factors of Competitivity—COMPETE, by the Portuguese Foundation for Science and Technology—EXCL/DTP-PIC/0069/2012 (Eugenia Carvalho), PEst-C/SAU/LA0001/2013 (CNC-Eugenia Carvalho), the Grupo de Estudo de Investigação Fundamental e Translacional/Sociedade Portuguesa de Diabetologia (Eugenia Carvalho), the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000 (Elisabet Børsheim and Eugenia Carvalho) and the P30 AG028718 (Elisabet Børsheim).

Author Contributions

João Moura and Eugenia Carvalho conceived and wrote the manuscript. João Moura, Elisabet Børsheim and Eugenia Carvalho revised the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Chen, L.; Magliano, D.J.; Zimmet, P.Z. The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat. Rev. Endocrinol. 2012, 8, 228–236. [Google Scholar]
  2. Whiting, D.R.; Guariguata, L.; Weil, C.; Shaw, J. Idf diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract. 2011, 94, 311–321. [Google Scholar] [PubMed]
  3. Moura, L.I.; Dias, A.M.; Carvalho, E.; de Sousa, H.C. Recent advances on the development of wound dressings for diabetic foot ulcer treatment—A review. Acta Biomater. 2013, 9, 7093–7114. [Google Scholar] [PubMed]
  4. Reaven, G.M. Pathophysiology of insulin resistance in human disease. Physiol. Rev. 1995, 75, 473–486. [Google Scholar] [PubMed]
  5. DeFronzo, R.A.; Bonadonna, R.C.; Ferrannini, E. Pathogenesis of niddm. A balanced overview. Diabetes Care 1992, 15, 318–368. [Google Scholar] [PubMed]
  6. Fontbonne, A.; Eschwege, E.; Cambien, F.; Richard, J.L.; Ducimetiere, P.; Thibult, N.; Warnet, J.M.; Claude, J.R.; Rosselin, G.E. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the paris prospective study. Diabetologia 1989, 32, 300–304. [Google Scholar] [PubMed]
  7. Srikanth, S.; Deedwania, P. Primary and secondary prevention strategy for cardiovascular disease in diabetes mellitus. Cardiol. Clin. 2011, 29, 47–70. [Google Scholar] [PubMed]
  8. Yun, J.S.; Ko, S.H.; Kim, J.H.; Moon, K.W.; Park, Y.M.; Yoo, K.D.; Ahn, Y.B. Diabetic retinopathy and endothelial dysfunction in patients with type 2 diabetes mellitus. Diabetes Metab. J. 2013, 37, 262–269. [Google Scholar] [PubMed]
  9. Klein, R.; Moss, S.E.; Klein, B.E.; Davis, M.D.; DeMets, D.L. Wisconsin epidemiologic study of diabetic retinopathy. XII. Relationship of c-peptide and diabetic retinopathy. Diabetes 1990, 39, 1445–1450. [Google Scholar] [PubMed]
  10. Andersen, A.R.; Christiansen, J.S.; Andersen, J.K.; Kreiner, S.; Deckert, T. Diabetic nephropathy in type 1 (insulin-dependent) diabetes: An epidemiological study. Diabetologia 1983, 25, 496–501. [Google Scholar] [PubMed]
  11. Higgins, G.C.; Coughlan, M.T. Mitochondrial dysfunction and mitophagy: The beginning and end to diabetic nephropathy? Br. J. Pharmacol. 2014, 171, 1917–1942. [Google Scholar]
  12. Kim, S.K.; Lee, K.J.; Hahm, J.R.; Lee, S.M.; Jung, T.S.; Jung, J.H.; Kim, S.; Kim, D.R.; Ahn, S.K.; Choi, W.H.; et al. Clinical significance of the presence of autonomic and vestibular dysfunction in diabetic patients with peripheral neuropathy. Diabetes Metab. J. 2012, 36, 64–69. [Google Scholar] [PubMed]
  13. Da Silva, L.; Carvalho, E.; Cruz, M.T. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin. Biol. Ther. 2010, 10, 1427–1439. [Google Scholar] [PubMed]
  14. Hata, J.; Arima, H.; Zoungas, S.; Fulcher, G.; Pollock, C.; Adams, M.; Watson, J.; Joshi, R.; Kengne, A.P.; Ninomiya, T.; et al. Effects of the endpoint adjudication process on the results of a randomised controlled trial: The advance trial. PLoS ONE 2013, 8, e55807. [Google Scholar] [PubMed]
  15. OʼConnor, P.J.; Ismail-Beigi, F. Near-normalization of glucose and microvascular diabetes complications: Data from accord and advance. Ther. Adv. Endocrinol. Metab. 2011, 2, 17–26. [Google Scholar]
  16. Bianchi, C.; Del Prato, S. Metabolic memory and individual treatment aims in type 2 diabetes-outcome-lessons learned from large clinical trials. Rev. Diabet. Stud. 2011, 8, 432–440. [Google Scholar] [PubMed]
  17. Holman, R.R.; Paul, S.K.; Bethel, M.A.; Matthews, D.R.; Neil, H.A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 2008, 359, 1577–1589. [Google Scholar] [PubMed]
  18. Gaede, P.; Lund-Andersen, H.; Parving, H.H.; Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 2008, 358, 580–591. [Google Scholar] [PubMed]
  19. Ambros, V. The functions of animal microRNAs. Nature 2004, 431, 350–355. [Google Scholar] [PubMed]
  20. Bartel, D.P. MicroRNAs: Target recognition and regulatory functions. Cell 2009, 136, 215–233. [Google Scholar] [PubMed]
  21. Maqbool, R.; Hussain, M.U. MicroRNAs and human diseases: Diagnostic and therapeutic potential. Cell Tissue Res. 2014. [Google Scholar] [CrossRef]
  22. Ardekani, A.M.; Naeini, M.M. The role of microRNAs in human diseases. Avicenna J. Med. Biotechnol. 2010, 2, 161–179. [Google Scholar] [PubMed]
  23. Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75, 843–854. [Google Scholar]
  24. Pillai, R.S.; Bhattacharyya, S.N.; Filipowicz, W. Repression of protein synthesis by miRNAs: How many mechanisms? Trends Cell Biol. 2007, 17, 118–126. [Google Scholar]
  25. Li, L.C.; Okino, S.T.; Zhao, H.; Pookot, D.; Place, R.F.; Urakami, S.; Enokida, H.; Dahiya, R. Small dsRNAs induce transcriptional activation in human cells. Proc. Natl. Acad. Sci. USA 2006, 103, 17337–17342. [Google Scholar] [PubMed]
  26. Vasudevan, S.; Tong, Y.; Steitz, J.A. Switching from repression to activation: MicroRNAs can up-regulate translation. Science 2007, 318, 1931–1934. [Google Scholar] [PubMed]
  27. Chew, B.H.; Ghazali, S.S.; Ismail, M.; Haniff, J.; Bujang, M.A. Age ≥60 years was an independent risk factor for diabetes-related complications despite good control of cardiovascular risk factors in patients with type 2 diabetes mellitus. Exp. Gerontol. 2013, 48, 485–491. [Google Scholar] [PubMed]
  28. Djaberi, R.; Beishuizen, E.D.; Pereira, A.M.; Rabelink, T.J.; Smit, J.W.; Tamsma, J.T.; Huisman, M.V.; Jukema, J.W. Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus. Diabetologia 2008, 51, 1581–1593. [Google Scholar] [PubMed]
  29. Rawal, S.; Manning, P.; Katare, R. Cardiovascular microRNAs: As modulators and diagnostic biomarkers of diabetic heart disease. Cardiovasc. Diabetol. 2014, 13, 44. [Google Scholar]
  30. Cheng, J.; Zhang, W.; Zhang, X.; Han, F.; Li, X.; He, X.; Li, Q.; Chen, J. Effect of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: A meta-analysis. JAMA Intern. Med. 2014, 174, 773–785. [Google Scholar] [PubMed]
  31. Davis, T.M.; Coleman, R.L.; Holman, R.R.; Group, U. Ethnicity and long-term vascular outcomes in type 2 diabetes: A prospective observational study (UKPDS 83). Diabetic Med. 2014, 31, 200–207. [Google Scholar]
  32. McClelland, A.D.; Kantharidis, P. MicroRNA in the development of diabetic complications. Clin. Sci. 2014, 126, 95–110. [Google Scholar] [PubMed]
  33. Kantharidis, P.; Wang, B.; Carew, R.M.; Lan, H.Y. Diabetes complications: The microRNA perspective. Diabetes 2011, 60, 1832–1837. [Google Scholar]
  34. Sayed, A.S.; Xia, K.; Salma, U.; Yang, T.; Peng, J. Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Heart Lung Circ. 2014, 23, 503–510. [Google Scholar] [PubMed]
  35. De Rosa, S.; Curcio, A.; Indolfi, C. Emerging role of microRNAs in cardiovascular diseases. Circ. J. 2014, 78, 567–575. [Google Scholar] [PubMed]
  36. Briasoulis, A.; Tousoulis, D.; Vogiatzi, G.; Siasos, G.; Papageorgiou, N.; Oikonomou, E.; Genimata, V.; Konsola, T.; Stefanadis, C. MicroRNAs: Biomarkers for cardiovascular disease in patients with diabetes mellitus. Curr. Top. Med. Chem. 2013, 13, 1533–1539. [Google Scholar] [PubMed]
  37. Shantikumar, S.; Caporali, A.; Emanueli, C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc. Res. 2012, 93, 583–593. [Google Scholar] [PubMed]
  38. Ruiz, M.A.; Chakrabarti, S. MicroRNAs: The underlying mediators of pathogenetic processes in vascular complications of diabetes. Can. J. Diabetes 2013, 37, 339–344. [Google Scholar] [PubMed]
  39. Vickers, K.C.; Rye, K.A.; Tabet, F. MicroRNAs in the onset and development of cardiovascular disease. Clin. Sci. 2014, 126, 183–194. [Google Scholar] [PubMed]
  40. Jaguszewski, M.; Osipova, J.; Ghadri, J.R.; Napp, L.C.; Widera, C.; Franke, J.; Fijalkowski, M.; Nowak, R.; Fijalkowska, M.; Volkmann, I.; et al. A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction. Eur. Heart J. 2014, 35, 999–1006. [Google Scholar] [PubMed]
  41. Gupta, M.K.; Halley, C.; Duan, Z.H.; Lappe, J.; ViteRNA, J.; Jana, S.; Augoff, K.; Mohan, M.L.; Vasudevan, N.T.; Na, J.; et al. MiRNA-548c: A specific signature in circulating pbmcs from dilated cardiomyopathy patients. J. Mol. Cell Cardiol. 2013, 62, 131–141. [Google Scholar]
  42. Huang, Z.P.; Chen, J.; Seok, H.Y.; Zhang, Z.; Kataoka, M.; Hu, X.; Wang, D.Z. MicroRNA-22 regulates cardiac hypertrophy and remodeling in response to stress. Circ. Res. 2013, 112, 1234–1243. [Google Scholar] [PubMed]
  43. Bang, C.; Batkai, S.; Dangwal, S.; Gupta, S.K.; Foinquinos, A.; Holzmann, A.; Just, A.; Remke, J.; Zimmer, K.; Zeug, A.; et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 2014, 124, 2136–2146. [Google Scholar] [PubMed]
  44. Reaven, G.M. Multiple chd risk factors in type 2 diabetes: Beyond hyperglycaemia. Diabetes Obes. Metab. 2002, 4, S13–S18. [Google Scholar] [PubMed]
  45. Kuwahata, S.; Fujita, S.; Orihara, K.; Hamasaki, S.; Oba, R.; Hirai, H.; Nagata, K.; Ishida, S.; Kataoka, T.; Oketani, N.; et al. High expression level of toll-like receptor 2 on monocytes is an important risk factor for arteriosclerotic disease. Atherosclerosis 2010, 209, 248–254. [Google Scholar] [PubMed]
  46. Weiner, S.D.; Ahmed, H.N.; Jin, Z.; Cushman, M.; Herrington, D.M.; Nelson, J.C.; di Tullio, M.R.; Homma, S. Systemic inflammation and brachial artery endothelial function in the multi-ethnic study of atherosclerosis (mesa). Heart 2014. [Google Scholar] [CrossRef]
  47. Xiao, L.; Liu, Y.; Wang, N. New paradigms in inflammatory signaling in vascular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 2014, 306, H317–H325. [Google Scholar] [PubMed]
  48. Wang, L.; Yang, Y.; Hong, B. Advances in the role of microRNAs in lipid metabolism-related anti-atherosclerotic drug discovery. Expert Opin. Drug Discov. 2013, 8, 977–990. [Google Scholar] [PubMed]
  49. Zampetaki, A.; Dudek, K.; Mayr, M. Oxidative stress in atherosclerosis: The role of microRNAs in arterial remodeling. Free Radic. Biol. Med. 2013, 64, 69–77. [Google Scholar] [PubMed]
  50. Magenta, A.; Greco, S.; Gaetano, C.; Martelli, F. Oxidative stress and microRNAs in vascular diseases. Int. J. Mol. Sci. 2013, 14, 17319–17346. [Google Scholar] [PubMed]
  51. Zernecke, A. MicroRNAs in the regulation of immune cell functions—Implications for atherosclerotic vascular disease. Thromb. Haemost. 2012, 107, 626–633. [Google Scholar] [PubMed]
  52. Busch, M.; Zernecke, A. MicroRNAs in the regulation of dendritic cell functions in inflammation and atherosclerosis. J. Mol. Med. 2012, 90, 877–885. [Google Scholar] [PubMed]
  53. Raitoharju, E.; Oksala, N.; Lehtimaki, T. MicroRNAs in the atherosclerotic plaque. Clin. Chem. 2013, 59, 1708–1721. [Google Scholar] [PubMed]
  54. Siasos, G.; Kollia, C.; Tsigkou, V.; Basdra, E.K.; Lymperi, M.; Oikonomou, E.; Kokkou, E.; Korompelis, P.; Papavassiliou, A.G. MicroRNAs: Novel diagnostic and prognostic biomarkers in atherosclerosis. Curr. Top. Med. Chem. 2013, 13, 1503–1517. [Google Scholar] [PubMed]
  55. Leung, A.; Natarajan, R. Noncoding RNAs in vascular disease. Curr. Opin. Cardiol. 2014, 29, 199–206. [Google Scholar] [PubMed]
  56. Menghini, R.; Stohr, R.; Federici, M. MicroRNAs in vascular aging and atherosclerosis. Ageing Res. Rev. 2014. [Google Scholar] [CrossRef]
  57. Weber, M.; Kim, S.; Patterson, N.; Rooney, K.; Searles, C.D. MiRNA-155 targets myosin light chain kinase and modulates actin cytoskeleton organization in endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 2014, 306, H1192–H1203. [Google Scholar] [PubMed]
  58. Tian, F.J.; An, L.N.; Wang, G.K.; Zhu, J.Q.; Li, Q.; Zhang, Y.Y.; Zeng, A.; Zou, J.; Zhu, R.F.; Han, X.S.; et al. Elevated microRNA-155 promotes foam cell formation by targeting hbp1 in atherogenesis. Cardiovasc. Res. 2014. [Google Scholar] [CrossRef]
  59. Hu, Y.W.; Hu, Y.R.; Zhao, J.Y.; Li, S.F.; Ma, X.; Wu, S.G.; Lu, J.B.; Qiu, Y.R.; Sha, Y.H.; Wang, Y.C.; et al. An agomir of mir-144-3p accelerates plaque formation through impairing reverse cholesterol transport and promoting pro-inflammatory cytokine production. PLoS One 2014, 9, e94997. [Google Scholar] [PubMed]
  60. Yang, Q.; Yang, K.; Li, A. MicroRNA21 protects against ischemiareperfusion and hypoxiareperfusioninduced cardiocyte apoptosis via the phosphatase and tensin homolog/aktdependent mechanism. Mol. Med. Rep. 2014, 9, 2213–2220. [Google Scholar] [PubMed]
  61. Pan, Y.; Liang, H.; Liu, H.; Li, D.; Chen, X.; Li, L.; Zhang, C.Y.; Zen, K. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor. J. Immunol. 2014, 192, 437–446. [Google Scholar] [PubMed]
  62. Vinod, M.; Chennamsetty, I.; Colin, S.; Belloy, L.; de Paoli, F.; Schaider, H.; Graier, W.F.; Frank, S.; Kratky, D.; Staels, B.; et al. Mir-206 controls lxralpha expression and promotes lxr-mediated cholesterol efflux in macrophages. Biochim. Biophys. Acta 2014, 1841, 827–835. [Google Scholar] [PubMed]
  63. Ying, C.; Sui-Xin, L.; Kang-Ling, X.; Wen-Liang, Z.; Lei, D.; Yuan, L.; Fan, Z.; Chen, Z. MicroRNA-492 reverses high glucose-induced insulin resistance in huvec cells through targeting resistin. Mol. Cell. Biochem. 2014, 391, 117–125. [Google Scholar] [PubMed]
  64. Stephenson, J.; Fuller, J.H. Microvascular and acute complications in iddm patients: The eurodiab iddm complications study. Diabetologia 1994, 37, 278–285. [Google Scholar] [PubMed]
  65. Scanlon, P.H.; Aldington, S.J.; Stratton, I.M. Epidemiological issues in diabetic retinopathy. Middle East Afr. J. Ophthalmol. 2013, 20, 293–300. [Google Scholar] [PubMed]
  66. Papavasileiou, E.; Dereklis, D.; Oikonomidis, P.; Grixti, A.; Vineeth Kumar, B.; Prasad, S. An effective programme to systematic diabetic retinopathy screening in order to reduce diabetic retinopathy blindness. Hellenic J. Nucl. Med. 2014, 17, S30–S34. [Google Scholar]
  67. Kato, M.; Castro, N.E.; Natarajan, R. MicroRNAs: Potential mediators and biomarkers of diabetic complications. Free Radic. Biol. Med. 2013, 64, 85–94. [Google Scholar] [PubMed]
  68. Xiong, F.; Du, X.; Hu, J.; Li, T.; Du, S.; Wu, Q. Altered retinal microRNA expression profiles in early diabetic retinopathy: An in silico analysis. Curr. Eye Res. 2014, 39, 720–729. [Google Scholar] [PubMed]
  69. Kovacs, B.; Lumayag, S.; Cowan, C.; Xu, S. MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats. Invest. Ophthalmol. Vis. Sci. 2011, 52, 4402–4409. [Google Scholar] [PubMed]
  70. Hou, Q.; Tang, J.; Wang, Z.; Wang, C.; Chen, X.; Hou, L.; Dong, X.D.; Tu, L. Inhibitory effect of microRNA-34a on retinal pigment epithelial cell proliferation and migration. Invest. Ophthalmol. Vis. Sci. 2013, 54, 6481–6488. [Google Scholar]
  71. Jindal, V. Neurodegeneration as a primary change and role of neuroprotection in diabetic retinopathy. Mol. Neurobiol. 2014. [Google Scholar] [CrossRef]
  72. Li, X.; Zhang, M.; Zhou, H. The morphological features and mitochondrial oxidative stress mechanism of the retinal neurons apoptosis in early diabetic rats. J. Diabetes Res. 2014, 2014, 678123. [Google Scholar] [PubMed]
  73. Silva, V.A.; Polesskaya, A.; Sousa, T.A.; Correa, V.M.; Andre, N.D.; Reis, R.I.; Kettelhut, I.C.; Harel-Bellan, A.; de Lucca, F.L. Expression and cellular localization of microRNA-29b and rax, an activator of the RNA-dependent protein kinase (pkr), in the retina of streptozotocin-induced diabetic rats. Mol. Vis. 2011, 17, 2228–2240. [Google Scholar] [PubMed]
  74. Chen, X.; Ye, S.; Xiao, W.; Luo, L.; Liu, Y. Differentially expressed microRNAs in tgfbeta2-induced epithelial-mesenchymal transition in retinal pigment epithelium cells. Int. J. Mol. Med. 2014, 33, 1195–1200. [Google Scholar] [PubMed]
  75. Cheng, H.C.; Ho, T.C.; Chen, S.L.; Lai, H.Y.; Hong, K.F.; Tsao, Y.P. Troglitazone suppresses transforming growth factor beta-mediated fibrogenesis in retinal pigment epithelial cells. Mol. Vis. 2008, 14, 95–104. [Google Scholar] [PubMed]
  76. Mortuza, R.; Feng, B.; Chakrabarti, S. Mir-195 regulates sirt1-mediated changes in diabetic retinopathy. Diabetologia 2014, 57, 1037–1046. [Google Scholar] [PubMed]
  77. Bento, C.F.; Fernandes, R.; Matafome, P.; Sena, C.; Seica, R.; Pereira, P. Methylglyoxal-induced imbalance in the ratio of vascular endothelial growth factor to angiopoietin 2 secreted by retinal pigment epithelial cells leads to endothelial dysfunction. Exp. Physiol. 2010, 95, 955–970. [Google Scholar] [PubMed]
  78. Ling, S.; Birnbaum, Y.; Nanhwan, M.K.; Thomas, B.; Bajaj, M.; Ye, Y. MicroRNA-dependent cross-talk between vegf and hif1alpha in the diabetic retina. Cell. Signal. 2013, 25, 2840–2847. [Google Scholar] [PubMed]
  79. Ye, P.; Liu, J.; He, F.; Xu, W.; Yao, K. Hypoxia-induced deregulation of mir-126 and its regulative effect on vegf and mmp-9 expression. Int. J. Med. Sci. 2014, 11, 17–23. [Google Scholar] [PubMed]
  80. Murray, A.R.; Chen, Q.; Takahashi, Y.; Zhou, K.K.; Park, K.; Ma, J.X. MicroRNA-200b downregulates oxidation resistance 1 (oxr1) expression in the retina of type 1 diabetes model. Invest. Ophthalmol. Vis. Sci. 2013, 54, 1689–1697. [Google Scholar] [PubMed]
  81. McArthur, K.; Feng, B.; Wu, Y.; Chen, S.; Chakrabarti, S. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy. Diabetes 2011, 60, 1314–1323. [Google Scholar] [PubMed]
  82. Gohda, T.; Mima, A.; Moon, J.Y.; Kanasaki, K. Combat diabetic nephropathy: From pathogenesis to treatment. J. Diabetes Res. 2014, 2014, 207140. [Google Scholar] [PubMed]
  83. Bichu, P.; Nistala, R.; Khan, A.; Sowers, J.R.; Whaley-Connell, A. Angiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: Results from the amadeo study. Vasc. Health Risk Manag. 2009, 5, 129–140. [Google Scholar] [PubMed]
  84. Collins, A.J.; Foley, R.N.; Herzog, C.; Chavers, B.; Gilbertson, D.; Ishani, A.; Kasiske, B.; Liu, J.; Mau, L.W.; McBean, M.; et al. United states renal data system 2008 annual data report. Am. J. Kidney Dis. 2009, 53, S1–S374. [Google Scholar] [PubMed]
  85. Alvarez, M.L.; Distefano, J.K. The role of non-coding RNAs in diabetic nephropathy: Potential applications as biomarkers for disease development and progression. Diabetes Res. Clin. Pract. 2013, 99, 1–11. [Google Scholar] [PubMed]
  86. Macisaac, R.J.; Ekinci, E.I.; Jerums, G. Markers of and risk factors for the development and progression of diabetic kidney disease. Am. J. Kidney Dis. 2014, 63, S39–S62. [Google Scholar] [PubMed]
  87. Jalal, D.I.; Rivard, C.J.; Johnson, R.J.; Maahs, D.M.; McFann, K.; Rewers, M.; Snell-Bergeon, J.K. Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: Findings from the coronary artery calcification in type 1 diabetes study. Nephrol. Dial. Transplant. 2010, 25, 1865–1869. [Google Scholar] [PubMed]
  88. Acosta, J.B.; del Barco, D.G.; Vera, D.C.; Savigne, W.; Lopez-Saura, P.; Guillen Nieto, G.; Schultz, G.S. The pro-inflammatory environment in recalcitrant diabetic foot wounds. Int. Wound J. 2008, 5, 530–539. [Google Scholar] [PubMed]
  89. Lin, C.L.; Hsu, Y.C.; Lee, P.H.; Lei, C.C.; Wang, J.Y.; Huang, Y.T.; Wang, S.Y.; Wang, F.S. Cannabinoid receptor 1 disturbance of PPARγ2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli. J. Mol. Med. 2014, 92, 779–792. [Google Scholar] [PubMed]
  90. Bocci, V.; Zanardi, I.; Huijberts, M.S.; Travagli, V. An integrated medical treatment for type-2 diabetes. Diabetes Metab. Syndr. 2014, 8, 57–61. [Google Scholar] [PubMed]
  91. Tan, S.M.; Sharma, A.; Stefanovic, N.; Yuen, D.Y.; Karagiannis, T.C.; Meyer, C.; Ward, K.W.; Cooper, M.E.; de Haan, J.B. A derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner, lessens diabetes-associated atherosclerosis and improves diabetic kidney disease. Diabetes 2014, 63, 3091–3103. [Google Scholar] [PubMed]
  92. Acikgoz, Y.; Can, B.; Bek, K.; Acikgoz, A.; Ozkaya, O.; Genc, G.; Sarikaya, S. The effect of simvastatin and erythropoietin on renal fibrosis in rats with unilateral ureteral obstruction. Renal Fail. 2014, 36, 252–257. [Google Scholar]
  93. Brennan, E.; McEvoy, C.; Sadlier, D.; Godson, C.; Martin, F. The genetics of diabetic nephropathy. Genes (Basel) 2013, 4, 596–619. [Google Scholar]
  94. McClelland, A.; Hagiwara, S.; Kantharidis, P. Where are we in diabetic nephropathy: MicroRNAs and biomarkers? Curr. Opin. Nephrol. Hypertens. 2014, 23, 80–86. [Google Scholar] [CrossRef]
  95. Khella, H.W.; Bakhet, M.; Lichner, Z.; Romaschin, A.D.; Jewett, M.A.; Yousef, G.M. MicroRNAs in kidney disease: An emerging understanding. Am. J. Kidney Dis. 2013, 61, 798–808. [Google Scholar] [PubMed]
  96. Chandrasekaran, K.; Karolina, D.S.; Sepramaniam, S.; Armugam, A.; Wintour, E.M.; Bertram, J.F.; Jeyaseelan, K. Role of microRNAs in kidney homeostasis and disease. Kidney Int. 2012, 81, 617–627. [Google Scholar] [PubMed]
  97. Srivastava, S.P.; Koya, D.; Kanasaki, K. MicroRNAs in kidney fibrosis and diabetic nephropathy: Roles on emt and endmt. Biomed. Res. Int. 2013, 2013, 125469. [Google Scholar] [PubMed]
  98. Kato, M.; Park, J.T.; Natarajan, R. MicroRNAs and the glomerulus. Exp. Cell Res. 2012, 318, 993–1000. [Google Scholar] [PubMed]
  99. Liang, M.; Liu, Y.; Mladinov, D.; Cowley, A.W., Jr.; Trivedi, H.; Fang, Y.; Xu, X.; Ding, X.; Tian, Z. MicroRNA: A new frontier in kidney and blood pressure research. Am. J. Physiol. Renal. Physiol. 2009, 297, F553–F558. [Google Scholar] [PubMed]
  100. Hagiwara, S.; McClelland, A.; Kantharidis, P. MicroRNA in diabetic nephropathy: Renin angiotensin, age/rage, and oxidative stress pathway. J. Diabetes Res. 2013, 2013, 173783. [Google Scholar] [PubMed]
  101. Lan, H.Y. Transforming growth factor-beta/smad signalling in diabetic nephropathy. Clin. Exp. Pharmacol. Physiol. 2012, 39, 731–738. [Google Scholar] [PubMed]
  102. Zhang, L.; He, S.; Guo, S.; Xie, W.; Xin, R.; Yu, H.; Yang, F.; Qiu, J.; Zhang, D.; Zhou, S.; et al. Down-regulation of mir-34a alleviates mesangial proliferation in vitro and glomerular hypertrophy in early diabetic nephropathy mice by targeting gas1. J. Diabetes Complicat. 2014, 28, 259–264. [Google Scholar] [PubMed]
  103. Lin, C.L.; Lee, P.H.; Hsu, Y.C.; Lei, C.C.; Ko, J.Y.; Chuang, P.C.; Huang, Y.T.; Wang, S.Y.; Wu, S.L.; Chen, Y.S.; et al. MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction. J. Am. Soc. Nephrol. 2014. [Google Scholar] [CrossRef]
  104. DiStefano, J.K.; Taila, M.; Alvarez, M.L. Emerging roles for miRNAs in the development, diagnosis, and treatment of diabetic nephropathy. Curr. Diab. Rep. 2013, 13, 582–591. [Google Scholar]
  105. Cachia, M.J.; Peakman, M.; Zanone, M.; Watkins, P.J.; Vergani, D. Reproducibility and persistence of neural and adrenal autoantibodies in diabetic autonomic neuropathy. Diabetic Med. 1997, 14, 461–465. [Google Scholar] [PubMed]
  106. Kostev, K.; Jockwig, A.; Hallwachs, A.; Rathmann, W. Prevalence and risk factors of neuropathy in newly diagnosed type 2 diabetes in primary care practices: A retrospective database analysis in germany and uk. Prim. Care Diabetes 2014, 8, 250–255. [Google Scholar] [PubMed]
  107. Callaghan, B.C.; Cheng, H.T.; Stables, C.L.; Smith, A.L.; Feldman, E.L. Diabetic neuropathy: Clinical manifestations and current treatments. Lancet Neurol. 2012, 11, 521–534. [Google Scholar] [PubMed]
  108. Tesfaye, S.; Boulton, A.J.; Dyck, P.J.; Freeman, R.; Horowitz, M.; Kempler, P.; Lauria, G.; Malik, R.A.; Spallone, V.; Vinik, A.; et al. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010, 33, 2285–2293. [Google Scholar] [PubMed]
  109. Tellechea, A.; Kafanas, A.; Leal, E.C.; Tecilazich, F.; Kuchibhotla, S.; Auster, M.E.; Kontoes, I.; Paolino, J.; Carvalho, E.; Nabzdyk, L.P.; et al. Increased skin inflammation and blood vessel density in human and experimental diabetes. Int. J. Low Extrem. Wounds 2013, 12, 4–11. [Google Scholar] [PubMed]
  110. Deli, G.; Bosnyak, E.; Pusch, G.; Komoly, S.; Feher, G. Diabetic neuropathies: Diagnosis and management. Neuroendocrinology 2013, 98, 267–280. [Google Scholar] [PubMed]
  111. Bansal, V.; Kalita, J.; Misra, U.K. Diabetic neuropathy. Postgrad. Med. J. 2006, 82, 95–100. [Google Scholar] [PubMed]
  112. Malik, R.; Veves, A.; Tesfaye, S.; Smith, G.; Cameron, N.; Zochodne, D.; Lauria, G.; The Toronto Consensus Panel on Diabetic Neuropathy. Small fiber neuropathy: Role in the diagnosis of diabetic sensorimotor polyneuropathy. Diabetes Metab. Res. Rev. 2011. [Google Scholar] [CrossRef]
  113. Daemen, M.A.; Kurvers, H.A.; Kitslaar, P.J.; Slaaf, D.W.; Bullens, P.H.; van den Wildenberg, F.A. Neurogenic inflammation in an animal model of neuropathic pain. Neurol. Res. 1998, 20, 41–45. [Google Scholar] [PubMed]
  114. Pradhan Nabzdyk, L.; Kuchibhotla, S.; Guthrie, P.; Chun, M.; Auster, M.E.; Nabzdyk, C.; Deso, S.; Andersen, N.; Gnardellis, C.; LoGerfo, F.W.; et al. Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J. Vasc. Surg. 2013, 58, 766–775. [Google Scholar] [PubMed]
  115. Moura, L.I.; Dias, A.M.; Leal, E.C.; Carvalho, L.; de Sousa, H.C.; Carvalho, E. Chitosan-based dressings loaded with neurotensin—An efficient strategy to improve early diabetic wound healing. Acta Biomater. 2014, 10, 843–857. [Google Scholar] [PubMed]
  116. Bali, K.K.; Hackenberg, M.; Lubin, A.; Kuner, R.; Devor, M. Sources of individual variability: MiRNAs that predispose to neuropathic pain identified using genome-wide sequencing. Mol. Pain 2014, 10, 22. [Google Scholar] [PubMed]
  117. Li, H.; Huang, Y.; Ma, C.; Yu, X.; Zhang, Z.; Shen, L. Mir-203 involves in neuropathic pain development and represses rap1a expression in nerve growth factor differentiated neuronal PC12 cells. Clin. J. Pain 2014. [Google Scholar] [CrossRef]
  118. Chen, H.P.; Zhou, W.; Kang, L.M.; Yan, H.; Zhang, L.; Xu, B.H.; Cai, W.H. Intrathecal mir-96 inhibits nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury. Neurochem. Res. 2014, 39, 76–83. [Google Scholar] [PubMed]
  119. Sakai, A.; Saitow, F.; Miyake, N.; Miyake, K.; Shimada, T.; Suzuki, H. Mir-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability. Brain 2013, 136, 2738–2750. [Google Scholar] [PubMed]
  120. Ciccacci, C.; Morganti, R.; di Fusco, D.; DʼAmato, C.; Cacciotti, L.; Greco, C.; Rufini, S.; Novelli, G.; Sangiuolo, F.; Marfia, G.A.; et al. Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes. Acta Diabetol. 2014, 51, 673–671. [Google Scholar] [PubMed]
  121. Zhou, S.; Gao, R.; Hu, W.; Qian, T.; Wang, N.; Ding, G.; Ding, F.; Yu, B.; Gu, X. Mir-9 inhibits schwann cell migration by targeting cthrc1 following sciatic nerve injury. J. Cell Sci. 2014, 127, 967–976. [Google Scholar] [PubMed]
  122. Gupta, S.K.; Singh, S.K. Diabetic foot: A continuing challenge. Adv. Exp. Med. Biol. 2012, 771, 123–138. [Google Scholar] [PubMed]
  123. Lu, M.H.; Hu, C.J.; Chen, L.; Peng, X.; Chen, J.; Hu, J.Y.; Teng, M.; Liang, G.P. Mir-27b represses migration of mouse mscs to burned margins and prolongs wound repair through silencing SDF-1a. PLoS ONE 2013, 8, e68972. [Google Scholar] [PubMed]
  124. Wang, J.M.; Tao, J.; Chen, D.D.; Cai, J.J.; Irani, K.; Wang, Q.; Yuan, H.; Chen, A.F. MicroRNA mir-27b rescues bone marrow-derived angiogenic cell function and accelerates wound healing in type 2 diabetes mellitus. Arterioscler Thromb Vasc. Biol. 2014, 34, 99–109. [Google Scholar] [PubMed]
  125. Meisgen, F.; Xu Landen, N.; Bouez, C.; Zuccolo, M.; Gueniche, A.; Stahle, M.; Sonkoly, E.; Breton, L.; Pivarcsi, A. Activation of toll-like receptors alters the microRNA expression profile of keratinocytes. Exp. Dermatol. 2014, 23, 281–283. [Google Scholar] [PubMed]
  126. Ning, M.S.; Andl, T. Control by a hairʼs breadth: The role of microRNAs in the skin. Cell Mol. Life Sci. 2013, 70, 1149–1169. [Google Scholar]
  127. Schneider, M.R. MicroRNAs as novel players in skin development, homeostasis and disease. Br. J. Dermatol. 2012, 166, 22–28. [Google Scholar] [PubMed]
  128. Moura, L.I.; Cruz, M.T.; Carvalho, E. The effect of neurotensin in human keratinocytes—Implication on impaired wound healing in diabetes. Exp. Biol. Med. (Maywood) 2014, 239, 6–12. [Google Scholar]
  129. Moura, L.I.; Silva, L.; Leal, E.C.; Tellechea, A.; Cruz, M.T.; Carvalho, E. Neurotensin modulates the migratory and inflammatory response of macrophages under hyperglycemic conditions. Biomed. Res. Int. 2013, 2013, 941764. [Google Scholar] [PubMed]
  130. Rodero, M.P.; Khosrotehrani, K. Skin wound healing modulation by macrophages. Int. J. Clin. Exp. Pathol. 2010, 3, 643–653. [Google Scholar] [PubMed]
  131. Rot, A.; von Andrian, U.H. Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells. Ann. Rev. Immunol. 2004, 22, 891–928. [Google Scholar]
  132. Le, Y.; Yang, Y.; Cui, Y.; Yazawa, H.; Gong, W.; Qiu, C.; Wang, J.M. Receptors for chemotactic formyl peptides as pharmacological targets. Int. Immunopharmacol. 2002, 2, 1–13. [Google Scholar] [PubMed]
  133. Zhai, Y.; Zhong, Z.; Chen, C.Y.; Xia, Z.; Song, L.; Blackburn, M.R.; Shyu, A.B. Coordinated changes in mRNA turnover, translation, and RNA processing bodies in bronchial epithelial cells following inflammatory stimulation. Mol. Cell Biol. 2008, 28, 7414–7426. [Google Scholar] [PubMed]
  134. Nakamachi, Y.; Kawano, S.; Takenokuchi, M.; Nishimura, K.; Sakai, Y.; Chin, T.; Saura, R.; Kurosaka, M.; Kumagai, S. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheumatol. 2009, 60, 1294–1304. [Google Scholar]
  135. Dorhoi, A.; Iannaccone, M.; Farinacci, M.; Fae, K.C.; Schreiber, J.; Moura-Alves, P.; Nouailles, G.; Mollenkopf, H.J.; Oberbeck-Muller, D.; Jorg, S.; et al. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J. Clin. Invest. 2013, 123, 4836–4848. [Google Scholar] [PubMed]
  136. Pradhan, L.; Cai, X.; Wu, S.; Andersen, N.D.; Martin, M.; Malek, J.; Guthrie, P.; Veves, A.; Logerfo, F.W. Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J. Surg. Res. 2011, 167, 336–342. [Google Scholar] [PubMed]
  137. Galkowska, H.; Wojewodzka, U.; Olszewski, W.L. Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regener. 2006, 14, 558–565. [Google Scholar]
  138. Min, M.; Peng, L.; Yang, Y.; Guo, M.; Wang, W.; Sun, G. MicroRNA-155 is involved in the pathogenesis of ulcerative colitis by targeting FOXO3a. Inflammatory Bowel Dis. 2014, 20, 652–659. [Google Scholar]
  139. Fabbri, E.; Borgatti, M.; Montagner, G.; Bianchi, N.; Finotti, A.; Lampronti, I.; Bezzerri, V.; Dechecchi, M.C.; Cabrini, G.; Gambari, R. Expression of microRNA-93 and Interleukin-8 during pseudomonas aeruginosa mediated induction of pro-inflammatory responses. Am. J. Respir. Cell Mol. Biol. 2014, 50, 1144–1155. [Google Scholar] [PubMed]
  140. Zykova, S.N.; Jenssen, T.G.; Berdal, M.; Olsen, R.; Myklebust, R.; Seljelid, R. Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice. Diabetes 2000, 49, 1451–1458. [Google Scholar] [PubMed]
  141. Harris, T.A.; Yamakuchi, M.; Ferlito, M.; Mendell, J.T.; Lowenstein, C.J. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc. Natl. Acad. Sci. USA 2008, 105, 1516–1521. [Google Scholar] [PubMed]
  142. Ortega, F.J.; Mercader, J.M.; Moreno-Navarrete, J.M.; Rovira, O.; Guerra, E.; Esteve, E.; Xifra, G.; Martinez, C.; Ricart, W.; Rieusset, J.; et al. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care 2014, 67, 51375–51383. [Google Scholar]
  143. Zhang, T.; Lv, C.; Li, L.; Chen, S.; Liu, S.; Wang, C.; Su, B. Plasma mir-126 is a potential biomarker for early prediction of type 2 diabetes mellitus in susceptible individuals. Biomed. Res. Int. 2013, 2013, 761617. [Google Scholar] [PubMed]
  144. Dianzani, U.; Funaro, A.; DiFranco, D.; Garbarino, G.; Bragardo, M.; Redoglia, V.; Buonfiglio, D.; de Monte, L.B.; Pileri, A.; Malavasi, F. Interaction between endothelium and CD4+CD45RA+ lymphocytes. Role of the human CD38 molecule. J. Immunol. 1994, 153, 952–959. [Google Scholar] [PubMed]
  145. Jude, J.A.; Dileepan, M.; Subramanian, S.; Solway, J.; Panettieri, R.A., Jr.; Walseth, T.F.; Kannan, M.S. Mir-140-3p regulation of tnf-alpha-induced cd38 expression in human airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2012, 303, L460–L468. [Google Scholar] [PubMed]
  146. Collares, C.V.; Evangelista, A.F.; Xavier, D.J.; Rassi, D.M.; Arns, T.; Foss-Freitas, M.C.; Foss, M.C.; Puthier, D.; Sakamoto-Hojo, E.T.; Passos, G.A.; et al. Identifying common and specific microRNAs expressed in peripheral blood mononuclear cell of type 1, type 2, and gestational diabetes mellitus patients. BMC Res. Notes 2013, 6, 491. [Google Scholar] [PubMed]
  147. Shanmugam, N.; Reddy, M.A.; Natarajan, R. Distinct roles of heterogeneous nuclear ribonuclear protein k and microRNA-16 in cyclooxygenase-2 RNA stability induced by s100b, a ligand of the receptor for advanced glycation end products. J. Biol. Chem. 2008, 283, 36221–36233. [Google Scholar] [PubMed]
  148. Mokhtar, S.S.; Vanhoutte, P.M.; Leung, S.W.S.; Yusof, M.I.; Sulaiman, W.A.W.; Saad, A.Z.M.; Suppian, R.; Rasoo, A.H.G. Reduced expression of prostacyclin synthase and nitric oxide synthase in subcutaneous arteries of type 2 diabetic patients. Tohoku J. Exp. Med. 2013, 231, 217–222. [Google Scholar] [PubMed]
  149. Matouskova, P.; Bartikova, H.; Bousova, I.; Hanusova, V.; Szotakova, B.; Skalova, L. Reference genes for real-time PCR quantification of messenger RNAs and microRNAs in mouse model of obesity. PLoS ONE 2014, 9, e86033. [Google Scholar] [PubMed]
  150. Ortega, F.J.; Mercader, J.M.; Catalan, V.; Moreno-Navarrete, J.M.; Pueyo, N.; Sabater, M.; Gomez-Ambrosi, J.; Anglada, R.; Fernandez-Formoso, J.A.; Ricart, W.; et al. Targeting the circulating microRNA signature of obesity. Clin. Chem. 2013, 59, 781–792. [Google Scholar] [PubMed]
  151. Nesca, V.; Guay, C.; Jacovetti, C.; Menoud, V.; Peyot, M.L.; Laybutt, D.R.; Prentki, M.; Regazzi, R. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 2013, 56, 2203–2212. [Google Scholar] [PubMed]
  152. Primo, M.N.; Bak, R.O.; Schibler, B.; Mikkelsen, J.G. Regulation of pro-inflammatory cytokines TNFα and IL24 by microRNA-203 in primary keratinocytes. Cytokine 2012, 60, 741–748. [Google Scholar] [PubMed]
  153. Mi, Q.; Riviere, B.; Clermont, G.; Steed, D.L.; Vodovotz, Y. Agent-based model of inflammation and wound healing: Insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1. Wound Repair Regener. 2007, 15, 671–682. [Google Scholar]
  154. Ennis, W.J.; Sui, A.; Bartholomew, A. Stem cells and healing: Impact on inflammation. Adv. Wound Care (New Rochelle) 2013, 2, 369–378. [Google Scholar]
  155. Xu, J.; Wu, W.; Zhang, L.; Dorset-Martin, W.; Morris, M.W.; Mitchell, M.E.; Liechty, K.W. The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: Correction with mesenchymal stem cell treatment. Diabetes 2012, 61, 2906–2912. [Google Scholar] [PubMed]
  156. Dickinson, S.; Hancock, D.P.; Petocz, P.; Ceriello, A.; Brand-Miller, J. High-glycemic index carbohydrate increases nuclear factor-κb activation in mononuclear cells of young, lean healthy subjects. Am. J. Clin. Nutr. 2008, 87, 1188–1193. [Google Scholar] [PubMed]
  157. Stegenga, M.E.; van der Crabben, S.N.; Dessing, M.C.; Pater, J.M.; van den Pangaart, P.S.; de Vos, A.F.; Tanck, M.W.; Roos, D.; Sauerwein, H.P.; van der Poll, T. Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans. Diabetic Med. 2008, 25, 157–164. [Google Scholar] [PubMed]
  158. Bogdanski, P.; Pupek-Musialik, D.; Dytfeld, J.; Jagodzinski, P.P.; Jablecka, A.; Kujawa, A.; Musialik, K. Influence of insulin therapy on expression of chemokine receptor CCR5 and selected inflammatory markers in patients with type 2 diabetes mellitus. Int. J. Clin. Pharmacol. Ther. 2007, 45, 563–567. [Google Scholar] [PubMed]
  159. Balasubramanyam, M.; Aravind, S.; Gokulakrishnan, K.; Prabu, P.; Sathishkumar, C.; Ranjani, H.; Mohan, V. Impaired MIR-146a expression links subclinical inflammation and insulin resistance in type 2 diabetes. Mol. Cell Biochem. 2011, 351, 197–205. [Google Scholar] [PubMed]
  160. Tellechea, A.; Leal, E.; Veves, A.; Cravalho, E. Inflammatory and angiogenic abnormalities in diabetic wound healing: Role of neuropeptides and therapeutic perspectives. Open Circ. Vasc. J. 2010, 3, 43–55. [Google Scholar]
  161. Pottier, N.; Maurin, T.; Chevalier, B.; Puissegur, M.P.; Lebrigand, K.; Robbe-Sermesant, K.; Bertero, T.; Lino Cardenas, C.L.; Courcot, E.; Rios, G.; et al. Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: Implication in epithelial-mesenchymal interactions. PLoS ONE 2009, 4, e6718. [Google Scholar] [PubMed]
  162. Corral-Fernandez, N.E.; Salgado-Bustamante, M.; Martinez-Leija, M.E.; Cortez-Espinosa, N.; Garcia-Hernandez, M.H.; Reynaga-Hernandez, E.; Quezada-Calvillo, R.; Portales-Perez, D.P. Dysregulated MIR-155 expression in peripheral blood mononuclear cells from patients with type 2 diabetes. Exp. Clin. Endocrinol. Diabetes 2013, 121, 347–353. [Google Scholar] [PubMed]
  163. Kishore, R.; Verma, S.K.; Mackie, A.R.; Vaughan, E.E.; Abramova, T.V.; Aiko, I.; Krishnamurthy, P. Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts. PLoS One 2013, 8, e60161. [Google Scholar] [PubMed]
  164. Madhyastha, R.; Madhyastha, H.; Nakajima, Y.; Omura, S.; Maruyama, M. MicroRNA signature in diabetic wound healing: Promotive role of MIR-21 in fibroblast migration. Int. Wound J. 2012, 9, 355–361. [Google Scholar] [PubMed]
  165. Delavary, B.M.; van der Veer, W.M.; van Egmond, M.; Niessen, F.B.; Beelen, R.H. Macrophages in skin injury and repair. Immunobiology 2011, 216, 753–762. [Google Scholar] [PubMed]
  166. Brancato, S.K.; Albina, J.E. Wound macrophages as key regulators of repair: Origin, phenotype, and function. Am. J. Pathol. 2011, 178, 19–25. [Google Scholar] [PubMed]
  167. Meng, S.; Cao, J.T.; Zhang, B.; Zhou, Q.; Shen, C.X.; Wang, C.Q. Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene spred-1. J. Mol. Cell Cardiol. 2012, 53, 64–72. [Google Scholar] [PubMed]
  168. Meng, S.; Cao, J.; Zhang, X.; Fan, Y.; Fang, L.; Wang, C.; Lv, Z.; Fu, D.; Li, Y. Downregulation of microRNA-130a contributes to endothelial progenitor cell dysfunction in diabetic patients via its target Runx3. PLoS ONE 2013, 8, e68611. [Google Scholar] [PubMed]
  169. Wang, C.H.; Lee, D.Y.; Deng, Z.; Jeyapalan, Z.; Lee, S.C.; Kahai, S.; Lu, W.Y.; Zhang, Y.; Yang, B.B. MicroRNA mir-328 regulates zonation morphogenesis by targeting CD44 expression. PLoS ONE 2008, 3, e2420. [Google Scholar] [PubMed]
  170. Collares, C.; Evangelista, A.; Xavier, D.; Macedo, C.; Rassi, D.; Foss-Freitas, M.; Foss, M.; Sakamoto-Hojo, E.; Passos, G.; Donadi, E. Meta-analysis of differentially expressed microRNAs in type 1, type 2 and gestational diabetes mellitus. Endocrine Abstracts 2012, 29, OC17.6. [Google Scholar]
  171. Caporali, A.; Emanueli, C. MicroRNA-503 and the extended microRNA-16 family in angiogenesis. Trends Cardiovasc. Med. 2011, 21, 162–166. [Google Scholar]
  172. Jordan, S.D.; Kruger, M.; Willmes, D.M.; Redemann, N.; Wunderlich, F.T.; Bronneke, H.S.; Merkwirth, C.; Kashkar, H.; Olkkonen, V.M.; Bottger, T.; et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated akt activation and impairs glucose metabolism. Nat. Cell Biol. 2011, 13, 434–446. [Google Scholar] [PubMed]
  173. Blumensatt, M.; Greulich, S.; de Wiza, D.H.; Mueller, H.; Maxhera, B.; Rabelink, M.J.; Hoeben, R.C.; Akhyari, P.; Al-Hasani, H.; Ruige, J.B.; et al. Activin a impairs insulin action in cardiomyocytes via up-regulation of mir-143. Cardiovasc. Res. 2013, 100, 201–210. [Google Scholar] [PubMed]
  174. Kohlstedt, K.; Trouvain, C.; Boettger, T.; Shi, L.; Fisslthaler, B.; Fleming, I. Amp-activated protein kinase regulates endothelial cell angiotensin-converting enzyme expression via p53 and the post-transcriptional regulation of microRNA-143/145. Circ. Res. 2013, 112, 1150–1158. [Google Scholar] [PubMed]
  175. Wang, S.; Aurora, A.B.; Johnson, B.A.; Qi, X.; McAnally, J.; Hill, J.A.; Richardson, J.A.; Bassel-Duby, R.; Olson, E.N. The endothelial-specific microRNA mir-126 governs vascular integrity and angiogenesis. Dev. Cell 2008, 15, 261–271. [Google Scholar] [PubMed]
  176. Van Solingen, C.; Seghers, L.; Bijkerk, R.; Duijs, J.M.; Roeten, M.K.; van Oeveren-Rietdijk, A.M.; Baelde, H.J.; Monge, M.; Vos, J.B.; de Boer, H.C.; et al. Antagomir-mediated silencing of endothelial cell specific microRNA-126 impairs ischemia-induced angiogenesis. J. Cell Mol. Med. 2009, 13, 1577–1585. [Google Scholar] [PubMed]
  177. Pastar, I.; Khan, A.A.; Stojadinovic, O.; Lebrun, E.A.; Medina, M.C.; Brem, H.; Kirsner, R.S.; Jimenez, J.J.; Leslie, C.; Tomic-Canic, M. Induction of specific microRNAs inhibits cutaneous wound healing. J. Biol. Chem. 2012, 287, 29324–29335. [Google Scholar] [PubMed]
  178. Sundaram, G.M.; Common, J.E.; Gopal, F.E.; Srikanta, S.; Lakshman, K.; Lunny, D.P.; Lim, T.C.; Tanavde, V.; Lane, E.B.; Sampath, P. “See-saw” expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature 2013, 495, 103–106. [Google Scholar] [PubMed]
  179. Bertero, T.; Gastaldi, C.; Bourget-Ponzio, I.; Imbert, V.; Loubat, A.; Selva, E.; Busca, R.; Mari, B.; Hofman, P.; Barbry, P.; et al. Mir-483-3p controls proliferation in wounded epithelial cells. FASEB J. 2011, 25, 3092–3105. [Google Scholar] [PubMed]
  180. Viticchie, G.; Lena, A.M.; Cianfarani, F.; Odorisio, T.; Annicchiarico-Petruzzelli, M.; Melino, G.; Candi, E. MicroRNA-203 contributes to skin re-epithelialization. Cell Death Dis. 2012, 3, e435. [Google Scholar] [PubMed]
  181. Ferland-McCollough, D.; Fernandez-Twinn, D.S.; Cannell, I.G.; David, H.; Warner, M.; Vaag, A.A.; Bork-Jensen, J.; Brons, C.; Gant, T.W.; Willis, A.E.; et al. Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death Differ. 2012, 19, 1003–1012. [Google Scholar] [PubMed]
  182. Hildebrand, J.; Rutze, M.; Walz, N.; Gallinat, S.; Wenck, H.; Deppert, W.; Grundhoff, A.; Knott, A. A comprehensive analysis of microRNA expression during human keratinocyte differentiation in vitro and in vivo. J. Invest. Dermatol. 2011, 131, 20–29. [Google Scholar] [PubMed]
  183. Nielsen, L.B.; Wang, C.; Sorensen, K.; Bang-Berthelsen, C.H.; Hansen, L.; Andersen, M.L.; Hougaard, P.; Juul, A.; Zhang, C.Y.; Pociot, F.; et al. Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: Evidence that mir-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp. Diabetes Res. 2012, 2012, 896362. [Google Scholar] [PubMed]
  184. Greco, S.; Fasanaro, P.; Castelvecchio, S.; DʼAlessandra, Y.; Arcelli, D.; di Donato, M.; Malavazos, A.; Capogrossi, M.C.; Menicanti, L.; Martelli, F. MicroRNA dysregulation in diabetic ischemic heart failure patients. Diabetes 2012, 61, 1633–1641. [Google Scholar]
  185. Yang, X.; Wang, J.; Guo, S.L.; Fan, K.J.; Li, J.; Wang, Y.L.; Teng, Y.; Yang, X. Mir-21 promotes keratinocyte migration and re-epithelialization during wound healing. Int. J. Biol. Sci. 2011, 7, 685–690. [Google Scholar] [PubMed]
  186. Wang, T.; Feng, Y.; Sun, H.; Zhang, L.; Hao, L.; Shi, C.; Wang, J.; Li, R.; Ran, X.; Su, Y.; et al. Mir-21 regulates skin wound healing by targeting multiple aspects of the healing process. Am. J. Pathol. 2012, 181, 1911–1920. [Google Scholar] [PubMed]
  187. Zeng, J.; Xiong, Y.; Li, G.; Liu, M.; He, T.; Tang, Y.; Chen, Y.; Cai, L.; Jiang, R.; Tao, J. Mir-21 is overexpressed in response to high glucose and protects endothelial cells from apoptosis. Exp. Clin. Endocrinol. Diabetes 2013, 121, 425–430. [Google Scholar] [PubMed]
  188. Chakraborty, C.; George Priya Doss, C.; Bandyopadhyay, S. MiRNAs in insulin resistance and diabetes-associated pancreatic cancer: The “minute and miracle” molecule moving as a monitor in the “genomic galaxy”. Curr. Drug Targets 2013, 14, 1110–1117. [Google Scholar]
  189. Jin, Y.; Tymen, S.D.; Chen, D.; Fang, Z.J.; Zhao, Y.; Dragas, D.; Dai, Y.; Marucha, P.T.; Zhou, X. MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing. PLoS ONE 2013, 8, e64434. [Google Scholar] [PubMed]
  190. Adam, L.; Zhong, M.; Choi, W.; Qi, W.; Nicoloso, M.; Arora, A.; Calin, G.; Wang, H.; Siefker-Radtke, A.; McConkey, D.; et al. Mir-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin. Cancer Res. 2009, 15, 5060–5072. [Google Scholar] [PubMed]
  191. Reddy, M.A.; Jin, W.; Villeneuve, L.; Wang, M.; Lanting, L.; Todorov, I.; Kato, M.; Natarajan, R. Pro-inflammatory role of microRNA-200 in vascular smooth muscle cells from diabetic mice. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 721–729. [Google Scholar] [PubMed]
  192. Costa, R.; Negrao, R.; Valente, I.; Castela, A.; Duarte, D.; Guardao, L.; Magalhaes, P.J.; Rodrigues, J.A.; Guimaraes, J.T.; Gomes, P.; et al. Xanthohumol modulates inflammation, oxidative stress, and angiogenesis in type 1 diabetic rat skin wound healing. J. Nat. Prod. 2013, 76, 2047–2053. [Google Scholar]
  193. Darby, I.A.; Bisucci, T.; Hewitson, T.D.; MacLellan, D.G. Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice. Int. J. Biochem. Cell Biol. 1997, 29, 191–200. [Google Scholar] [PubMed]
  194. Lin, A.; Hokugo, A.; Nishimura, I. Wound closure and wound management: A new therapeutic molecular target. Cell Adh. Migr. 2010, 4, 396–399. [Google Scholar] [PubMed]
  195. Honda, N.; Jinnin, M.; Kajihara, I.; Makino, T.; Makino, K.; Masuguchi, S.; Fukushima, S.; Okamoto, Y.; Hasegawa, M.; Fujimoto, M.; et al. TGF-β-mediated downregulation of microRNA-196a contributes to the constitutive upregulated type i collagen expression in scleroderma dermal fibroblasts. J. Immunol. 2012, 188, 3323–3331. [Google Scholar] [PubMed]
  196. Kashiyama, K.; Mitsutake, N.; Matsuse, M.; Ogi, T.; Saenko, V.A.; Ujifuku, K.; Utani, A.; Hirano, A.; Yamashita, S. Mir-196a downregulation increases the expression of type i and iii collagens in keloid fibroblasts. J. Invest. Dermatol. 2012, 132, 1597–1604. [Google Scholar] [PubMed]
  197. Mori, M.; Nakagami, H.; Rodriguez-Araujo, G.; Nimura, K.; Kaneda, Y. Essential role for mir-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 2012, 10, e1001314. [Google Scholar] [PubMed]
  198. Moura, J.; da Silva, L.; Cruz, M.T.; Carvalho, E. Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: Potential benefits for wound healing. Arch. Dermatol. Res. 2013, 305, 557–569. [Google Scholar] [PubMed]
  199. Munz, B.; Tretter, Y.P.; Hertel, M.; Engelhardt, F.; Alzheimer, C.; Werner, S. The roles of activins in repair processes of the skin and the brain. Mol. Cell Endocrinol. 2001, 180, 169–177. [Google Scholar] [PubMed]
  200. Wu, H.; Wu, M.; Chen, Y.; Allan, C.A.; Phillips, D.J.; Hedger, M.P. Correlation between blood activin levels and clinical parameters of type 2 diabetes. Exp. Diabetes Res. 2012, 2012, 410579. [Google Scholar] [PubMed]
  201. Mizuno, Y.; Tokuzawa, Y.; Ninomiya, Y.; Yagi, K.; Yatsuka-Kanesaki, Y.; Suda, T.; Fukuda, T.; Katagiri, T.; Kondoh, Y.; Amemiya, T.; et al. Mir-210 promotes osteoblastic differentiation through inhibition of acvr1b. FEBS Lett 2009, 583, 2263–2268. [Google Scholar] [PubMed]
  202. Liu, Y.; Taylor, N.E.; Lu, L.; Usa, K.; Cowley, A.W., Jr.; Ferreri, N.R.; Yeo, N.C.; Liang, M. Renal medullary microRNAs in dahl salt-sensitive rats: Mir-29b regulates several collagens and related genes. Hypertension 2010, 55, 974–982. [Google Scholar] [PubMed]
  203. Cushing, L.; Kuang, P.P.; Qian, J.; Shao, F.; Wu, J.; Little, F.; Thannickal, V.J.; Cardoso, W.V.; Lu, J. Mir-29 is a major regulator of genes associated with pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 2011, 45, 287–294. [Google Scholar] [PubMed]
  204. Monaghan, M.; Browne, S.; Schenke-Layland, K.; Pandit, A. A collagen-based scaffold delivering exogenous microRNA-29b to modulate extracellular matrix remodeling. Mol. Ther. 2014, 22, 786–796. [Google Scholar] [PubMed]
  205. Shilo, S.; Roy, S.; Khanna, S.; Sen, C.K. MicroRNA in cutaneous wound healing: A new paradigm. DNA Cell Biol. 2007, 26, 227–237. [Google Scholar] [PubMed]
  206. Banerjee, J.; Sen, C.K. MicroRNAs in skin and wound healing. Methods Mol. Biol. 2013, 936, 343–356. [Google Scholar] [PubMed]
  207. Sand, M.; Gambichler, T.; Sand, D.; Skrygan, M.; Altmeyer, P.; Bechara, F.G. MicroRNAs and the skin: Tiny players in the bodyʼs largest organ. J. Dermatol. Sci. 2009, 53, 169–175. [Google Scholar] [PubMed]
  208. Motameny, S.; Wolters, S.; Nurnberg, P.; Schumacher, B. Next generation sequencing of miRNAs—Strategies, resources and methods. Genes (Basel) 2010, 1, 70–84. [Google Scholar]
  209. Pritchard, C.C.; Cheng, H.H.; Tewari, M. MicroRNA profiling: Approaches and considerations. Nat. Rev. Genet. 2012, 13, 358–369. [Google Scholar] [PubMed]
  210. Pelaez, P.; Trejo, M.S.; Iniguez, L.P.; Estrada-Navarrete, G.; Covarrubias, A.A.; Reyes, J.L.; Sanchez, F. Identification and characterization of microRNAs in phaseolus vulgaris by high-throughput sequencing. BMC Genet. 2012, 13, 83. [Google Scholar] [PubMed]
  211. Kong, L.; Zhu, J.; Han, W.; Jiang, X.; Xu, M.; Zhao, Y.; Dong, Q.; Pang, Z.; Guan, Q.; Gao, L.; et al. Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: A clinical study. Acta Diabetol. 2011, 48, 61–69. [Google Scholar] [PubMed]
  212. Guay, C.; Regazzi, R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat. Rev. Endocrinol. 2013, 9, 513–521. [Google Scholar] [PubMed]
  213. Farr, R.J.; Joglekar, M.V.; Taylor, C.J.; Hardikar, A.A. Circulating non-coding RNAs as biomarkers of beta cell death in diabetes. Pediatr. Endocrinol. Rev. 2013, 11, 14–20. [Google Scholar] [PubMed]
  214. Hulsmans, M.; Holvoet, P. MicroRNAs as early biomarkers in obesity and related metabolic and cardiovascular diseases. Curr. Pharm. Des. 2013, 19, 5704–5717. [Google Scholar]
  215. Takahashi, P.; Xavier, D.J.; Evangelista, A.F.; Manoel-Caetano, F.S.; Macedo, C.; Collares, C.V.; Foss-Freitas, M.C.; Foss, M.C.; Rassi, D.M.; Donadi, E.A.; et al. MicroRNA expression profiling and functional annotation analysis of their targets in patients with type 1 diabetes mellitus. Gene 2014, 539, 213–223. [Google Scholar] [PubMed]
  216. Salas-Perez, F.; Codner, E.; Valencia, E.; Pizarro, C.; Carrasco, E.; Perez-Bravo, F. MicroRNAs mir-21a and mir-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 2013, 218, 733–737. [Google Scholar]
  217. Baran-Gale, J.; Fannin, E.E.; Kurtz, C.L.; Sethupathy, P. Beta cell 5'-shifted isomirs are candidate regulatory hubs in type 2 diabetes. PLoS ONE 2013, 8, e73240. [Google Scholar] [PubMed]
  218. Al-Wahbi, A.M. Impact of a diabetic foot care education program on lower limb amputation rate. Vasc. Health Risk Manag. 2010, 6, 923–934. [Google Scholar] [PubMed]
  219. Game, F.L.; Hinchliffe, R.J.; Apelqvist, J.; Armstrong, D.G.; Bakker, K.; Hartemann, A.; Londahl, M.; Price, P.E.; Jeffcoate, W.J. A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab. Res. Rev. 2012, 28, S119–S141. [Google Scholar]
  220. Sieveking, D.P.; Ng, M.K. Cell therapies for therapeutic angiogenesis: Back to the bench. Vasc. Med. 2009, 14, 153–166. [Google Scholar] [PubMed]
  221. Kirana, S.; Stratmann, B.; Prante, C.; Prohaska, W.; Koerperich, H.; Lammers, D.; Gastens, M.H.; Quast, T.; Negrean, M.; Stirban, O.A.; et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int. J. Clin. Pract. 2012. [Google Scholar] [CrossRef]
  222. Shu, Y.; Pi, F.; Sharma, A.; Rajabi, M.; Haque, F.; Shu, D.; Leggas, M.; Evers, B.M.; Guo, P. Stable RNA nanoparticles as potential new generation drugs for cancer therapy. Adv. Drug Deliv. Rev. 2014, 66, 74–89. [Google Scholar] [PubMed]
  223. Park, C.Y.; Choi, Y.S.; McManus, M.T. Analysis of microRNA knockouts in mice. Hum. Mol. Genet. 2010, 19, R169–R175. [Google Scholar] [PubMed]
  224. Ruberti, F.; Barbato, C.; Cogoni, C. Targeting microRNAs in neurons: Tools and perspectives. Exp. Neurol. 2012, 235, 419–426. [Google Scholar] [PubMed]
  225. Van Solingen, C.; Araldi, E.; Chamorro-Jorganes, A.; Fernandez-Hernando, C.; Suarez, Y. Improved repair of dermal wounds in mice lacking microRNA-155. J. Cell Mol. Med. 2014. [Google Scholar] [CrossRef]
  226. Alipour, M.R.; Khamaneh, A.M.; Yousefzadeh, N.; Mohammad-nejad, D.; Soufi, F.G. Upregulation of microRNA-146a was not accompanied by downregulation of pro-inflammatory markers in diabetic kidney. Mol. Biol. Rep. 2013, 40, 6477–6483. [Google Scholar]
  227. Guo, Q.; Zhang, J.; Li, J.; Zou, L.; Zhang, J.; Xie, Z.; Fu, X.; Jiang, S.; Chen, G.; Jia, Q.; et al. Forced mir-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of fas in germinal center b cells. Blood 2013, 121, 4875–4883. [Google Scholar] [PubMed]

Share and Cite

MDPI and ACS Style

Moura, J.; Børsheim, E.; Carvalho, E. The Role of MicroRNAs in Diabetic Complications—Special Emphasis on Wound Healing. Genes 2014, 5, 926-956. https://doi.org/10.3390/genes5040926

AMA Style

Moura J, Børsheim E, Carvalho E. The Role of MicroRNAs in Diabetic Complications—Special Emphasis on Wound Healing. Genes. 2014; 5(4):926-956. https://doi.org/10.3390/genes5040926

Chicago/Turabian Style

Moura, João, Elisabet Børsheim, and Eugenia Carvalho. 2014. "The Role of MicroRNAs in Diabetic Complications—Special Emphasis on Wound Healing" Genes 5, no. 4: 926-956. https://doi.org/10.3390/genes5040926

Article Metrics

Back to TopTop