International Journal of Molecular Sciences

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Open AccessEditorial

Advances in the Pathogenesis of Diabetic Kidney Disease

by Christodoula Kourtidou and Konstantinos Tziomalos

Int. J. Mol. Sci. 2024, 25(8), 4563; https://doi.org/10.3390/ijms25084563 - 22 Apr 2024

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Abstract

Diabetic kidney disease (DKD) is both a frequent complication of diabetes mellitus (DM) [...] Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

Research

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13 pages, 1354 KiB

Open AccessArticle

Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy

by Hana Th. AlMajed, Mohamed Abu-Farha, Eman Alshawaf, Sriraman Devarajan, Zahra Alsairafi, Ashraf Elhelaly, Preethi Cherian, Irina Al-Khairi, Hamad Ali, Rose Mol Jose, Thangavel Alphonse Thanaraj, Ebaa Al-Ozairi, Fahd Al-Mulla, Abdulnabi Al Attar and Jehad Abubaker

Int. J. Mol. Sci. 2023, 24(18), 14244; https://doi.org/10.3390/ijms241814244 - 18 Sep 2023

Cited by 4 | Viewed by 1345

Abstract

Diabetic nephropathy (DN) is a complicated condition related to type 2 diabetes mellitus (T2D). ANGPTL8 is a hepatic protein highlighted as a risk factor for DN in patients with T2D; additionally, recent evidence from DN studies supports the involvement of growth hormone/IGF/IGF-binding protein [...] Read more.

Diabetic nephropathy (DN) is a complicated condition related to type 2 diabetes mellitus (T2D). ANGPTL8 is a hepatic protein highlighted as a risk factor for DN in patients with T2D; additionally, recent evidence from DN studies supports the involvement of growth hormone/IGF/IGF-binding protein axis constituents. The potential link between ANGPTL8 and IGFBPs in DN has not been explored before. Here, we assessed changes in the circulating ANGPTL8 levels in patients with DN and its association with IGFBP-1, -3, and -4. Our data revealed a significant rise in circulating ANGPTL8 in people with DN, 4443.35 ± 396 ng/mL compared to 2059.73 ± 216 ng/mL in people with T2D (p < 0.001). Similarly, levels of IGFBP-3 and -4 were significantly higher in people with DN compared to the T2D group. Interestingly, the rise in ANGPTL8 levels correlated positively with IGFBP-4 levels in T2DM patients with DN (p < 0.001) and this significant correlation disappeared in T2DM patients without DN. It also correlated positively with serum creatinine and negatively with the estimated glomerular filtration rate (eGFR, All < 0.05). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and IGFBP4 was 0.76 (0.69–0.84), p < 0.001, and the specificity was 85.9%. In conclusion, our results showed a significant increase in ANGPTL8 in patients with DN that correlated exclusively with IGFBP-4, implicating a potential role of both proteins in the pathophysiology of DN. Our findings highlight the significance of these biomarkers, suggesting them as promising diagnostic molecules for the detection of diabetic nephropathy. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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15 pages, 4376 KiB

Open AccessArticle

Exploratory Study Analyzing the Urinary Peptidome of T2DM Patients Suggests Changes in ECM but Also Inflammatory and Metabolic Pathways Following GLP-1R Agonist Treatment

by Sonnal Lohia, Justyna Siwy, Emmanouil Mavrogeorgis, Susanne Eder, Stefanie Thöni, Gert Mayer, Harald Mischak, Antonia Vlahou and Vera Jankowski

Int. J. Mol. Sci. 2023, 24(17), 13540; https://doi.org/10.3390/ijms241713540 - 31 Aug 2023

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Abstract

Type II diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes mellitus cases in the world. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while the underlying molecular mechanisms [...] Read more.

Type II diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes mellitus cases in the world. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients. Urine samples of thirty-two T2DM patients from the PROVALID study (“A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers”) collected pre- and post-treatment with GLP-1R agonist drugs were analyzed by CE-MS. In total, 70 urinary peptides were significantly affected by GLP-1R agonist treatment, generated from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides, was highlighted. Treatment also resulted in the downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR, and TTR, many of which were previously found to be associated with increased insulin resistance and inflammation. The findings indicate potential molecular mechanisms of GLP-1R agonists in the context of the management of T2DM and the prevention or delaying of the progression of its associated diseases. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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13 pages, 2955 KiB

Open AccessArticle

KITLG Promotes Glomerular Endothelial Cell Injury in Diabetic Nephropathy by an Autocrine Effect

by Jiun-Chi Huang, Szu-Chia Chen, Wei-An Chang, Wei-Wen Hung, Ping-Hsun Wu, Ling-Yu Wu, Jer-Ming Chang, Ya-Ling Hsu and Yi-Chun Tsai

Int. J. Mol. Sci. 2022, 23(19), 11723; https://doi.org/10.3390/ijms231911723 - 3 Oct 2022

Cited by 3 | Viewed by 2490

Abstract

Diabetic nephropathy (DN) is an increasing threat to human health. The impact of hyperglycemia or its metabolites, advanced glycation end-products (AGEs), on glomerular endothelial cells (GECs) and their pathophysiologic mechanisms are not well explored. Our results reveal that AGEs increased the expression and [...] Read more.

Diabetic nephropathy (DN) is an increasing threat to human health. The impact of hyperglycemia or its metabolites, advanced glycation end-products (AGEs), on glomerular endothelial cells (GECs) and their pathophysiologic mechanisms are not well explored. Our results reveal that AGEs increased the expression and secretion of the KIT ligand (KITLG) in GECs. Both AGEs and KITLG promoted endothelial-to-mesenchymal transition (EndoMT) in GECs and further increased the permeability of GECs through the AKT/extracellular-signal-regulated kinase pathway. Inhibition of KITLG’s effects by imatinib prevented AGE-medicated EndoMT in GECs, supporting the belief that KITLG is a critical factor for GEC injury. We found higher KITLG levels in the GECs and urine of db/db mice compared with db/m mice, and urinary KITLG levels were positively correlated with the urinary albumin-to-creatinine ratio (ACR). Furthermore, type 2 diabetic patients had higher urinary KITLG levels than normal individuals, as well as urinary KITLG levels that were positively correlated with urinary ACR and negatively correlated with the estimated glomerular filtration rate. KITLG plays a pathogenic role in GEC injury in DN and might act as a biomarker of DN progression. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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8 pages, 1667 KiB

Open AccessArticle

Fluorescence Imaging Using Enzyme-Activatable Probes for Detecting Diabetic Kidney Disease and Glomerular Diseases

by Kentaro Yamada, Tomoaki Takata, Takuji Iyama, Shintaro Hamada, Yukari Mae, Takaaki Sugihara and Hajime Isomoto

Int. J. Mol. Sci. 2022, 23(15), 8150; https://doi.org/10.3390/ijms23158150 - 24 Jul 2022

Cited by 6 | Viewed by 2131

Abstract

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of [...] Read more.

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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Review

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16 pages, 340 KiB

Open AccessReview

Experimental Models to Study Diabetes Mellitus and Its Complications: Limitations and New Opportunities

by Beatriz Martín-Carro, Javier Donate-Correa, Sara Fernández-Villabrille, Julia Martín-Vírgala, Sara Panizo, Natalia Carrillo-López, Laura Martínez-Arias, Juan F. Navarro-González, Manuel Naves-Díaz, José L. Fernández-Martín, Cristina Alonso-Montes and Jorge B. Cannata-Andía

Int. J. Mol. Sci. 2023, 24(12), 10309; https://doi.org/10.3390/ijms241210309 - 18 Jun 2023

Cited by 6 | Viewed by 4200

Abstract

Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. [...] Read more.

Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. This review will focus on the features, advantages and limitations of some of the most used DM models in rats, such as the spontaneous models: Bio-Breeding Diabetes-Prone (BB-DP) and LEW.1AR1-iddm, as representative models of type 1 DM (DM-1); the Zucker diabetic fatty (ZDF) and Goto-kakizaki (GK) rats, as representative models of type 2 DM (DM-2); and other models induced by surgical, dietary and pharmacological—alloxan and streptozotocin—procedures. Given the variety of DM models in rats, as well as the non-uniformity in the protocols and the absence of all the manifestation of the long-term multifactorial complications of DM in humans, the researchers must choose the one that best suits the final objectives of the study. These circumstances, added to the fact that most of the experimental research in the literature is focused on the study of the early phase of DM, makes it necessary to develop long-term studies closer to DM in humans. In this review, a recently published rat DM model induced by streptozotocin injection with chronic exogenous administration of insulin to reduce hyperglycaemia has also been included in an attempt to mimic the chronic phase of DM in humans. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

19 pages, 1594 KiB

Open AccessReview

Therapeutic Potential of Targeting Complement C5a Receptors in Diabetic Kidney Disease

by Inez A. Trambas, Melinda T. Coughlan and Sih Min Tan

Int. J. Mol. Sci. 2023, 24(10), 8758; https://doi.org/10.3390/ijms24108758 - 15 May 2023

Cited by 7 | Viewed by 3355

Abstract

Diabetic kidney disease (DKD) affects 30–40% of patients with diabetes and is currently the leading cause of end-stage renal disease (ESRD). The activation of the complement cascade, a highly conserved element of the innate immune system, has been implicated in the pathogenesis of [...] Read more.

Diabetic kidney disease (DKD) affects 30–40% of patients with diabetes and is currently the leading cause of end-stage renal disease (ESRD). The activation of the complement cascade, a highly conserved element of the innate immune system, has been implicated in the pathogenesis of diabetes and its complications. The potent anaphylatoxin C5a is a critical effector of complement-mediated inflammation. Excessive activation of the C5a-signalling axis promotes a potent inflammatory environment and is associated with mitochondrial dysfunction, inflammasome activation, and the production of reactive oxygen species. Conventional renoprotective agents used in the treatment of diabetes do not target the complement system. Mounting preclinical evidence indicates that inhibition of the complement system may prove protective in DKD by reducing inflammation and fibrosis. Targeting the C5a-receptor signaling axis is of particular interest, as inhibition at this level attenuates inflammation while preserving the critical immunological defense functions of the complement system. In this review, the important role of the C5a/C5a-receptor axis in the pathogenesis of diabetes and kidney injuries will be discussed, and an overview of the status and mechanisms of action of current complement therapeutics in development will be provided. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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12 pages, 746 KiB

Open AccessReview

Therapeutic Advances in Diabetic Kidney Disease

by Panagiotis I. Georgianos, Vasilios Vaios, Theodoros Eleftheriadis, Evangelos Papachristou and Vassilios Liakopoulos

Int. J. Mol. Sci. 2023, 24(3), 2803; https://doi.org/10.3390/ijms24032803 - 1 Feb 2023

Cited by 8 | Viewed by 4823

Abstract

Although sodium glucose co-transporter type 2 (SGLT-2) inhibitors were initially introduced as glucose-lowering medications, it was later discovered that cardiorenal protection is the most important treatment effect of these agents. A triad of landmark trials consistently showed the benefits of SGLT-2 inhibitors on [...] Read more.

Although sodium glucose co-transporter type 2 (SGLT-2) inhibitors were initially introduced as glucose-lowering medications, it was later discovered that cardiorenal protection is the most important treatment effect of these agents. A triad of landmark trials consistently showed the benefits of SGLT-2 inhibitors on kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD), irrespective of the presence or absence of Type 2 diabetes (T2D). Furthermore, finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that safely and effectively improved cardiorenal outcomes in a large Phase 3 clinical trial program that included >13,000 patients with T2D and a wide spectrum of CKD. These two drug categories have shared and distinct mechanisms of action, generating the hypothesis that an overadditive cardiorenal benefit with their combined use may be biologically plausible. In this article, we describe the mechanism of action, and we provide an overview of the evidence for cardiorenal protection with SGLT-2 inhibitors and the nonsteroidal MRA finerenone in patients with CKD associated with T2D. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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13 pages, 327 KiB

Open AccessPerspective

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

by Christodoula Kourtidou and Konstantinos Tziomalos

Int. J. Mol. Sci. 2023, 24(6), 6007; https://doi.org/10.3390/ijms24066007 - 22 Mar 2023

Cited by 9 | Viewed by 2219

Abstract

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears [...] Read more.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears to induce oxidative stress, inflammation and fibrosis in the diabetic kidney. In the present review, we summarize the current knowledge on the association between histone modification and DKD. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis of Diabetic Kidney Disease)

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