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Cellular and Molecular Research of Kidney Diseases
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Cellular and Molecular Research of Kidney Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 37759

Special Issue Editors

Dr. Marta Ruiz-Ortega

E-Mail Website
Guest Editor
Molecular and Cellular Biology in Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid Faculty of Medicine, 28049 Madrid, Spain
Interests: chronic kidney disease (CKD); acute kidney injury (AKI); cellular communication; epigenetic; metabolic reprogramming; signaling; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Sandra Rayego-Mateos

E-Mail Website
Guest Editor
Molecular and Cellular Biology in Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid Faculty of Medicine, Madrid, Spain
Interests: renal diseases; cardiovascular diseases; basic research; inflammation; fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Laura Marquez-Expósito

E-Mail Website
Guest Editor
Molecular and Cellular Biology in Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid Faculty of Medicine, Madrid, Spain
Interests: kidney pathology; inflamation; fibrosis; senescence; notch signaling pathway

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) represents a wide variety of diseases with different etiologies, including immunological, metabolic, genetic, vascular or mechanical-related complications, as well as an age-related disorder. CKD is the 5th predicted global cause of death by 2040, the fastest increase among major causes of death, after Alzheimer, revealing the importance of research in this area. Current CKD therapies are limited to harsh immunosuppression in some fast progressive diseases, as immune glomerulonephritis, as well as drugs blocking the renin angiotensin system aimed to control systemic blood pressure. Although, recent trials have reported promising results with SGLT2 inhibition, the majority of CKD patients still progress towards end-stage renal damage (ESRD) requiring renal replacement therapies, such as dialysis or transplantation.

Intensive research in this area includes investigation of cellular communication, phenotype changes, including those related to senescent phenotypes, novel mediators of kidney injury, epigenetic mechanisms, activation of signaling pathways, among others, showing the complexity of this field. Strategies to target resident glomerular or tubular damage, as well as immune cells have been proposed to ameliorate disease progression or even revert kidney damage. In spite of all available data, translation of new research into novel therapies in CKD is greatly lagging behind other disciplines.

We invite you to submit novel research about molecular and cellular mechanisms involved in kidney injury.

Dr. Marta Ruiz-Ortega
Dr. Sandra Rayego-Mateos
Dr. Laura Marquez-Expósito
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (15 papers)

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Research

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25 pages, 6334 KiB  
Article
Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells
by Graziano Colombo, Alessandra Altomare, Emanuela Astori, Lucia Landoni, Maria Lisa Garavaglia, Ranieri Rossi, Daniela Giustarini, Maria Chiara Lionetti, Nicoletta Gagliano, Aldo Milzani and Isabella Dalle-Donne
Int. J. Mol. Sci. 2023, 24(1), 691; https://doi.org/10.3390/ijms24010691 - 30 Dec 2022
Cited by 1 | Viewed by 2172
Abstract
Urea is the uremic toxin accumulating with the highest concentration in the plasma of chronic kidney disease (CKD) patients, not being completely cleared by dialysis. Urea accumulation is reported to exert direct and indirect side effects on the gastrointestinal tract, kidneys, adipocytes, and [...] Read more.
Urea is the uremic toxin accumulating with the highest concentration in the plasma of chronic kidney disease (CKD) patients, not being completely cleared by dialysis. Urea accumulation is reported to exert direct and indirect side effects on the gastrointestinal tract, kidneys, adipocytes, and cardiovascular system (CVS), although its pathogenicity is still questioned since studies evaluating its side effects lack homogeneity. Here, we investigated the effects of physiological and pathological urea concentrations on a human endothelial cell line from the microcirculation (Human Microvascular Endothelial Cells-1, HMEC-1). Urea (5 g/L) caused a reduction in the proliferation rate after 72 h of exposure and appeared to be a potential endothelial-to-mesenchymal transition (EndMT) stimulus. Moreover, urea induced actin filament rearrangement, a significant increase in matrix metalloproteinases 2 (MMP-2) expression in the medium, and a significant up- or down-regulation of other EndMT biomarkers (keratin, fibrillin-2, and collagen IV), as highlighted by differential proteomic analysis. Among proteins whose expression was found to be significantly dysregulated following exposure of HMEC-1 to urea, dimethylarginine dimethylaminohydrolase (DDAH) and vasorin turned out to be down-regulated. Both proteins have been directly linked to cardiovascular diseases (CVD) by in vitro and in vivo studies. Future experiments will be needed to deepen their role and investigate the signaling pathways in which they are involved to clarify the possible link between CKD and CVD. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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20 pages, 5135 KiB  
Article
Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
by José Luis Morgado-Pascual, Beatriz Suarez-Alvarez, Vanessa Marchant, Pamela Basantes, Pierre-Louis Tharaux, Alberto Ortiz, Carlos Lopez-Larrea, Marta Ruiz-Ortega and Sandra Rayego-Mateos
Int. J. Mol. Sci. 2023, 24(1), 486; https://doi.org/10.3390/ijms24010486 - 28 Dec 2022
Cited by 5 | Viewed by 2201
Abstract
Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among [...] Read more.
Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among these drugs, bromodomain and extra-terminal domain (BET) inhibitors (iBETs) have shown beneficial effects in experimental kidney disease and fibrotic disorders. Sex-determining region Y-box 9 (SOX9) is a transcription factor involved in regulating proliferation, migration, and regeneration, but its role in kidney fibrosis is still unclear. We investigated whether iBETs could regulate ECM accumulation in experimental GN and evaluated the role of SOX9 in this process. For this purpose, we tested the iBET JQ1 in mice with anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS). In NTS-injected mice, JQ1 treatment reduced glomerular ECM deposition, mainly by inhibiting glomerular COLIV accumulation and Col4a3 gene overexpression. Moreover, chromatin immunoprecipitation assays demonstrated that JQ1 inhibited the recruitment and binding of BRD4 to the Col4a3 promoter and reduced its transcription. Active SOX9 was found in the nuclei of glomerular cells of NTS-injured kidneys, mainly in COLIV-stained regions. JQ1 treatment blocked SOX9 nuclear translocation in injured kidneys. Moreover, in vitro JQ1 blocked TGF-β1-induced SOX9 activation and ECM production in cultured mesangial cells. Additionally, SOX9 gene silencing inhibited ECM production, including COLIV production. Our results demonstrated that JQ1 inhibited SOX9/COLIV, to reduce experimental glomerulosclerosis, supporting further research of iBET as a potential therapeutic option in progressive glomerulosclerosis. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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27 pages, 5066 KiB  
Article
miR−122−5p Regulates Renal Fibrosis In Vivo
by Shohei Kaneko, Katsunori Yanai, Hiroki Ishii, Akinori Aomatsu, Keiji Hirai, Susumu Ookawara, Kenichi Ishibashi and Yoshiyuki Morishita
Int. J. Mol. Sci. 2022, 23(23), 15423; https://doi.org/10.3390/ijms232315423 - 6 Dec 2022
Cited by 2 | Viewed by 2096
Abstract
The role of exogenous microRNAs (miRNAs) in renal fibrosis is poorly understood. Here, the effect of exogenous miRNAs on renal fibrosis was investigated using a renal fibrosis mouse model generated by unilateral ureteral obstruction (UUO). miRNA microarray analysis and quantitative reverse-transcription polymerase chain [...] Read more.
The role of exogenous microRNAs (miRNAs) in renal fibrosis is poorly understood. Here, the effect of exogenous miRNAs on renal fibrosis was investigated using a renal fibrosis mouse model generated by unilateral ureteral obstruction (UUO). miRNA microarray analysis and quantitative reverse-transcription polymerase chain reaction showed that miR−122−5p was the most downregulated (0.28-fold) miRNA in the kidneys of UUO mice. The injection of an miR−122−5p mimic promoted renal fibrosis and upregulated COL1A2 and FN1, whereas an miR−122−5p inhibitor suppressed renal fibrosis and downregulated COL1A2 and FN1. The expression levels of fibrosis-related mRNAs, which were predicted targets of miR−122−5p, were evaluated. The expression level of TGFBR2, a pro-fibrotic mRNA, was upregulated by the miR−122−5p mimic, and the expression level of FOXO3, an anti−fibrotic mRNA, was upregulated by the miR−122−5p inhibitor. The protein expressions of TGFBR2 and FOXO3 were confirmed by immunohistochemistry. Additionally, the expression levels of LC3, downstream anti-fibrotic mRNAs of FOXO3, were upregulated by the miR−122−5p inhibitor. These results suggest that miR−122−5p has critical roles in renal fibrosis. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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22 pages, 5170 KiB  
Article
Effect of Antibiotic Amphotericin B Combinations with Selected 1,3,4-Thiadiazole Derivatives on RPTECs in an In Vitro Model
by Agnieszka Dróżdż, Adrianna Sławińska-Brych, Dominika Kubera, Magdalena Kimsa-Dudek, Joanna Magdalena Gola, Jolanta Adamska, Celina Kruszniewska-Rajs, Arkadiusz Matwijczuk, Dariusz Karcz, Wojciech Dąbrowski, Andrzej Stepulak and Mariusz Gagoś
Int. J. Mol. Sci. 2022, 23(23), 15260; https://doi.org/10.3390/ijms232315260 - 3 Dec 2022
Cited by 3 | Viewed by 1593
Abstract
4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (C1) and 4-[5-(naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-yl] benzene1,3-diol (NTBD) are representative derivatives of the thiadiazole group, with a high antimycotic potential and minimal toxicity against normal human fibroblast cells. The present study has proved its ability to synergize with the antifungal activity of AmB. The [...] Read more.
4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (C1) and 4-[5-(naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-yl] benzene1,3-diol (NTBD) are representative derivatives of the thiadiazole group, with a high antimycotic potential and minimal toxicity against normal human fibroblast cells. The present study has proved its ability to synergize with the antifungal activity of AmB. The aim of this work was to evaluate the cytotoxic effects of C1 or NTBD, alone or in combination with AmB, on human renal proximal tubule epithelial cells (RPTECs) in vitro. Cell viability was assessed with the MTT assay. Flow cytometry and spectrofluorimetric techniques were used to assess the type of cell death and production of reactive oxygen species (ROS), respectively. The ELISA assay was performed to measure the caspase-2, -3, and -9 activity. ATR-FTIR spectroscopy was used to evaluate biomolecular changes in RPTECs induced by the tested formulas. The combinations of C1/NTBD and AmB did not exert a strong inhibitory effect on the viability/growth of kidney cells, as evidenced by the negligible changes in the apoptotic/necrotic rate and caspase activity, compared to the control cells. Both NTBD and C1 displayed stronger anti-oxidant activity when combined with AmB. The relatively low nephrotoxicity of the thiadiazole derivative combinations and the protective activity against AmB-induced oxidative stress may indicate their potential use in the therapy of fungal infections. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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13 pages, 5181 KiB  
Article
Kidney Cyst Lining Epithelial Cells Are Resistant to Low-Dose Cisplatin-Induced DNA Damage in a Preclinical Model of Autosomal Dominant Polycystic Kidney Disease
by Sayanthooran Saravanabavan and Gopala K. Rangan
Int. J. Mol. Sci. 2022, 23(20), 12547; https://doi.org/10.3390/ijms232012547 - 19 Oct 2022
Viewed by 1860
Abstract
Increased DNA damage response (DDR) signaling in kidney cyst-lining epithelial cells (CECs) may provide an opportunity for cell-specific therapeutic targeting in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inhibiting ataxia telangiectasia mutated (ATM; a proximal DDR kinase) together with low-dose cisplatin [...] Read more.
Increased DNA damage response (DDR) signaling in kidney cyst-lining epithelial cells (CECs) may provide an opportunity for cell-specific therapeutic targeting in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inhibiting ataxia telangiectasia mutated (ATM; a proximal DDR kinase) together with low-dose cisplatin overwhelms the DDR response and leads to selective apoptosis of cyst-lining epithelial cells (CECs). Pkd1RC/RC/Atm+/− mice were treated with either vehicle or a single low-dose cisplatin, and the acute effects on CECs (DNA damage and apoptosis) after 72 h and chronic effects on progression (cyst size, inflammation, fibrosis) after 3 weeks were investigated. At 72 h, cisplatin caused a dose-dependent increase in γH2AX-positive nuclei in both CECs and non-cystic tubules but did not cause selective apoptosis in Pkd1RC/RC/Atm+/− mice. Moreover, the increase in γH2AX-positive nuclei was 1.7-fold lower in CECs compared to non-cystic epithelial cells (p < 0.05). Low-dose cisplatin also did not alter long-term disease progression in Pkd1RC/RC/Atm+/− mice. In vitro, human ADPKD cyst-derived cell lines were also resistant to cisplatin (WT9-12: 61.7 ± 4.6%; WT9-7: 64.8 ± 2.7% cell viability) compared to HK-2 (25.1 ± 4.2%), and 3D cyst growth in MDCK cells was not altered. Finally, combined low-dose cisplatin with AZD0156 (an ATM inhibitor) non-selectively reduced γH2AX in both cystic and non-cystic tubular cells and exacerbated cystic kidney disease. In conclusion, these data suggest that CECs are resistant to DNA damage, and that the combination of cisplatin with ATM inhibitors is not an effective strategy for selectively eliminating kidney cysts in ADPKD. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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13 pages, 2023 KiB  
Article
Protective Effect of D-Panthenol in Rhabdomyolysis-Induced Acute Kidney Injury
by Dmitry S. Semenovich, Egor Y. Plotnikov, Elena P. Lukiyenko, Alexander A. Astrowski and Nina P. Kanunnikova
Int. J. Mol. Sci. 2022, 23(20), 12273; https://doi.org/10.3390/ijms232012273 - 14 Oct 2022
Cited by 3 | Viewed by 3767
Abstract
We investigated the nephroprotective effect of D-panthenol in rhabdomyolysis-induced acute kidney injury (AKI). Adult male Wistar rats were injected with 50% glycerol solution to induce rhabdomyolysis. Animals with rhabdomyolysis were injected with D-panthenol (200 mg/kg) for 7 days. On day 8, we examined [...] Read more.
We investigated the nephroprotective effect of D-panthenol in rhabdomyolysis-induced acute kidney injury (AKI). Adult male Wistar rats were injected with 50% glycerol solution to induce rhabdomyolysis. Animals with rhabdomyolysis were injected with D-panthenol (200 mg/kg) for 7 days. On day 8, we examined AKI markers, renal histology, antioxidant capacity, and protein glutathionylation in kidneys to uncover mechanisms of D-panthenol effects. Rhabdomyolysis kidneys were shown to have pathomorphological alterations (mononuclear infiltration, dilatation of tubules, and hyaline casts in Henle’s loops and collecting ducts). Activities of skeletal muscle damage markers (creatine kinase and lactate dehydrogenase) increased, myoglobinuria was observed, and creatinine, BUN, and pantetheinase activity in serum and urine rose. Signs of oxidative stress in the kidney tissue of rhabdomyolysis rats, increased levels of lipid peroxidation products, and activities of antioxidant enzymes (SOD, catalase, and glutathione peroxidase) were all alleviated by administration of D-panthenol. Its application improved kidney morphology and decreased AKI markers. Mechanisms of D-panthenol’s beneficial effects were associated with an increase in total coenzyme A levels, activity of Krebs cycle enzymes, and attenuation of protein glutathionylation. D-Panthenol protects kidneys from rhabdomyolysis-induced AKI through antioxidant effects, normalization of mitochondrial metabolism, and modulation of glutathione-dependent signaling. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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11 pages, 2080 KiB  
Article
Ojeoksan Ameliorates Cisplatin-Induced Acute Kidney Injury in Mice by Downregulating MAPK and NF-κB Pathways
by Dong-Uk Kim, Bitna Kweon, Jin-Young Oh, Chang-Seob Seo, Dong-Gu Kim, Hye-Yoom Kim, Ho-Sub Lee, Sung-Joo Park and Gi-Sang Bae
Int. J. Mol. Sci. 2022, 23(20), 12254; https://doi.org/10.3390/ijms232012254 - 14 Oct 2022
Cited by 1 | Viewed by 1724
Abstract
Acute kidney injury (AKI) is a major side effect of cisplatin, a crucial anticancer agent. Therefore, it is necessary to develop drugs to protect against cisplatin-induced nephrotoxicity. Ojeoksan (OJS), a traditional blended herbal prescription, is mostly used in Korea; however, there are no [...] Read more.
Acute kidney injury (AKI) is a major side effect of cisplatin, a crucial anticancer agent. Therefore, it is necessary to develop drugs to protect against cisplatin-induced nephrotoxicity. Ojeoksan (OJS), a traditional blended herbal prescription, is mostly used in Korea; however, there are no reports on the efficacy of OJS against cisplatin-induced AKI. To investigate the reno-protective effect of OJS on AKI, we orally administered 50, 100, and 200 mg/kg of OJS to mice 1 h before intraperitoneal injection with 20 mg/kg of cisplatin. OJS inhibited the increase of blood urea nitrogen (BUN) and serum creatinine (SCr) levels and reduced histological changes in the kidney, like loss of brush borders, renal tubular necrosis, and cast formation. Administration of OSJ reduced the levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. In addition, OJS inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways in cisplatin-induced AKI. These results suggest that OJS attenuates cisplatin-induced AKI by downregulating the MAPK and NF-κB pathways. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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13 pages, 1311 KiB  
Article
Impact of Acetate versus Citrate Dialysates on Intermediary Metabolism—A Targeted Metabolomics Approach
by José Jesús Broseta, Marta Roca, Diana Rodríguez-Espinosa, Luis Carlos López-Romero, Aina Gómez-Bori, Elena Cuadrado-Payán, Ramón Devesa-Such, Amparo Soldevila, Sergio Bea-Granell, Pilar Sánchez-Pérez and Julio Hernández-Jaras
Int. J. Mol. Sci. 2022, 23(19), 11693; https://doi.org/10.3390/ijms231911693 - 2 Oct 2022
Cited by 2 | Viewed by 1678
Abstract
Acetate is widely used as a dialysate buffer to avoid the precipitation of bicarbonate salts. However, even at low concentrations that wouldn’t surpass the metabolic capacity of the Krebs tricarboxylic acid (TCA) cycle, other metabolic routes are activated, leading to undesirable clinical consequences [...] Read more.
Acetate is widely used as a dialysate buffer to avoid the precipitation of bicarbonate salts. However, even at low concentrations that wouldn’t surpass the metabolic capacity of the Krebs tricarboxylic acid (TCA) cycle, other metabolic routes are activated, leading to undesirable clinical consequences by poorly understood mechanisms. This study aims to add information that could biologically explain the clinical improvements found in patients using citrate dialysate. A unicentric, cross-over, prospective targeted metabolomics study was designed to analyze the differences between two dialysates, one containing 4 mmol/L of acetate (AD) and the other 1 mmol/L of citrate (CD). Fifteen metabolites were studied to investigate changes induced in the TCA cycle, glycolysis, anaerobic metabolism, ketone bodies, and triglyceride and aminoacidic metabolism. Twenty-one patients completed the study. Citrate increased during the dialysis sessions when CD was used, without surpassing normal values. Other differences found in the next TCA cycle steps showed an increased substrate accumulation when using AD. While lactate decreased, pyruvate remained stable, and ketogenesis was boosted during dialysis. Acetylcarnitine and myo-inositol were reduced during dialysis, while glycerol remained constant. Lastly, glutamate and glutarate decreased due to the inhibition of amino acidic degradation. This study raises new hypotheses that need further investigation to understand better the biochemical processes that dialysis and the different dialysate buffers induce in the patient’s metabolism. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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13 pages, 4780 KiB  
Article
Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model
by Young-Ah Kim, Hyemin Gu, Mi-Gyeong Gwon, Hyun-Jin An, Seongjae Bae, Jaechan Leem, Hyun Jin Jung, Kwan-Kyu Park and Sun-Jae Lee
Int. J. Mol. Sci. 2022, 23(19), 11365; https://doi.org/10.3390/ijms231911365 - 26 Sep 2022
Viewed by 1623
Abstract
The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several [...] Read more.
The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring-type non-coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)-induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory-related markers (interleukin-1β, tumor necrosis factor-α), and that of fibrosis (α-smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy-related markers, microtubule-associated protein light chain 3, Beclin1, and autophagy-related gene 5-12. We confirmed that ring-type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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Review

Jump to: Research

15 pages, 718 KiB  
Review
The Role of MicroRNA in the Pathogenesis of Diabetic Nephropathy
by Joanna Szostak, Anna Gorący, Damian Durys, Paweł Dec, Andrzej Modrzejewski and Andrzej Pawlik
Int. J. Mol. Sci. 2023, 24(7), 6214; https://doi.org/10.3390/ijms24076214 - 25 Mar 2023
Cited by 8 | Viewed by 2297
Abstract
Diabetic nephropathy is one of the most common and severe complications of diabetes mellitus, affecting one in every five patients suffering from diabetes. Despite extensive research, the exact pathogenesis of diabetic nephropathy is still unclear. Several factors and pathways are known to be [...] Read more.
Diabetic nephropathy is one of the most common and severe complications of diabetes mellitus, affecting one in every five patients suffering from diabetes. Despite extensive research, the exact pathogenesis of diabetic nephropathy is still unclear. Several factors and pathways are known to be involved in the development of the disease, such as reactive oxygen species or the activation of the renin–angiotensin–aldosterone system. The expression of those proteins might be extensively regulated by microRNA. Recent research suggests that in diabetic nephropathy patients, the profile of miRNA is significantly changed. In this review, we focus on the actions of miRNA in various pathways involved in the pathogenesis of diabetic nephropathy and the clinical usage of miRNAs as biomarkers and therapeutic targets. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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15 pages, 919 KiB  
Review
The Effect of the Gut Microbiota on Transplanted Kidney Function
by Jarosław Przybyciński, Sylwester Drożdżal, Aleksandra Wilk, Violetta Dziedziejko, Kamila Szumilas and Andrzej Pawlik
Int. J. Mol. Sci. 2023, 24(2), 1260; https://doi.org/10.3390/ijms24021260 - 9 Jan 2023
Cited by 4 | Viewed by 2509
Abstract
The intestinal microflora is extremely important, not only in the processes of absorption, digestion and biosynthesis of vitamins, but also in shaping the immune and cognitive functions of the human body. Several studies demonstrate a correlation between microbiota composition and such events as [...] Read more.
The intestinal microflora is extremely important, not only in the processes of absorption, digestion and biosynthesis of vitamins, but also in shaping the immune and cognitive functions of the human body. Several studies demonstrate a correlation between microbiota composition and such events as graft rejection, kidney interstitial fibrosis, urinary tract infections, and diarrhoea or graft tolerance. Some of those changes might be directly linked with pathologies such as colonization with pathogenic bacterial strains. Gut microbiota composition also plays an important role in metabolic complications and viral infections after transplantation. From the other side, gut microbiota might induce graft tolerance by promotion of T and B regulatory cells. Graft tolerance induction is still an extremely important issue regarding transplantology and might allow the reduction or even avoidance of immunosuppressive treatment. Although there is a rising evidence of the pivotal role of gut microbiota in aspects of kidney transplantation there is still a lack of knowledge on the direct mechanisms of microbiota action. Furthermore, some of those negative effects could be reversed by probiotics of faecal microbiota trapoinsplantation. While diabetes and hypertension as well as BKV and CMV viremia are common and important complications of transplantation, both worsening the graft function and causing systemic injuries, it opens up potential clinical treatment options. As has been also suggested in the current review, some bacterial subsets exhibit protective properties. However, currently, there is a lack of evidence on pro- and prebiotic supplementation in kidney transplant patients. In the current review, we describe the effect of the microbiota on the transplanted kidney in renal transplant recipients. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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13 pages, 1585 KiB  
Review
The Optimization of Renal Graft Preservation Temperature to Mitigate Cold Ischemia-Reperfusion Injury in Kidney Transplantation
by Maria Abou Taka, George J. Dugbartey and Alp Sener
Int. J. Mol. Sci. 2023, 24(1), 567; https://doi.org/10.3390/ijms24010567 - 29 Dec 2022
Cited by 4 | Viewed by 2340
Abstract
Renal transplantation is the preferred treatment for patients with end-stage renal disease. The current gold standard of kidney preservation for transplantation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal ischemia-reperfusion injury (IRI), a pathological process that negatively impacts [...] Read more.
Renal transplantation is the preferred treatment for patients with end-stage renal disease. The current gold standard of kidney preservation for transplantation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal ischemia-reperfusion injury (IRI), a pathological process that negatively impacts graft survival and function. Recent efforts to mitigate cold renal IRI involve preserving renal grafts at higher or subnormothermic temperatures. These temperatures may be beneficial in reducing the risk of cold renal IRI, while also maintaining active biological processes such as increasing the expression of mitochondrial protective metabolites. In this review, we discuss different preservation temperatures for renal transplantation and pharmacological supplementation of kidney preservation solutions with hydrogen sulfide to determine an optimal preservation temperature to mitigate cold renal IRI and enhance renal graft function and recipient survival. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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26 pages, 1833 KiB  
Review
Roles of NAD+ in Acute and Chronic Kidney Diseases
by Marya Morevati, Evandro Fei Fang, Maria L. Mace, Mehmet Kanbay, Eva Gravesen, Anders Nordholm, Søren Egstrand and Mads Hornum
Int. J. Mol. Sci. 2023, 24(1), 137; https://doi.org/10.3390/ijms24010137 - 21 Dec 2022
Cited by 6 | Viewed by 4030
Abstract
Nicotinamide adenine dinucleotide (oxidized form, NAD+) is a critical coenzyme, with functions ranging from redox reactions and energy metabolism in mitochondrial respiration and oxidative phosphorylation to being a central player in multiple cellular signaling pathways, organ resilience, health, and longevity. Many [...] Read more.
Nicotinamide adenine dinucleotide (oxidized form, NAD+) is a critical coenzyme, with functions ranging from redox reactions and energy metabolism in mitochondrial respiration and oxidative phosphorylation to being a central player in multiple cellular signaling pathways, organ resilience, health, and longevity. Many of its cellular functions are executed via serving as a co-substrate for sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), and CD38. Kidney damage and diseases are common in the general population, especially in elderly persons and diabetic patients. While NAD+ is reduced in acute kidney injury (AKI) and chronic kidney disease (CKD), mounting evidence indicates that NAD+ augmentation is beneficial to AKI, although conflicting results exist for cases of CKD. Here, we review recent progress in the field of NAD+, mainly focusing on compromised NAD+ levels in AKI and its effect on essential cellular pathways, such as mitochondrial dysfunction, compromised autophagy, and low expression of the aging biomarker αKlotho (Klotho) in the kidney. We also review the compromised NAD+ levels in renal fibrosis and senescence cells in the case of CKD. As there is an urgent need for more effective treatments for patients with injured kidneys, further studies on NAD+ in relation to AKI/CKD may shed light on novel therapeutics. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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14 pages, 730 KiB  
Review
Exfoliated Kidney Cells from Urine for Early Diagnosis and Prognostication of CKD: The Way of the Future?
by Henry H. L. Wu, Ewa M. Goldys, Carol A. Pollock and Sonia Saad
Int. J. Mol. Sci. 2022, 23(14), 7610; https://doi.org/10.3390/ijms23147610 - 9 Jul 2022
Cited by 3 | Viewed by 3589
Abstract
Chronic kidney disease (CKD) is a global health issue, affecting more than 10% of the worldwide population. The current approach for formal diagnosis and prognostication of CKD typically relies on non-invasive serum and urine biomarkers such as serum creatinine and albuminuria. However, histological [...] Read more.
Chronic kidney disease (CKD) is a global health issue, affecting more than 10% of the worldwide population. The current approach for formal diagnosis and prognostication of CKD typically relies on non-invasive serum and urine biomarkers such as serum creatinine and albuminuria. However, histological evidence of tubulointerstitial fibrosis is the ‘gold standard’ marker of the likelihood of disease progression. The development of novel biomedical technologies to evaluate exfoliated kidney cells from urine for non-invasive diagnosis and prognostication of CKD presents opportunities to avoid kidney biopsy for the purpose of prognostication. Efforts to apply these technologies more widely in clinical practice are encouraged, given their potential as a cost-effective approach, and no risk of post-biopsy complications such as bleeding, pain and hospitalization. The identification of biomarkers in exfoliated kidney cells from urine via western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence techniques, measurement of cell and protein-specific messenger ribonucleic acid (mRNA)/micro-RNA and other techniques have been reported. Recent innovations such as multispectral autofluorescence imaging and single-cell RNA sequencing (scRNA-seq) have brought additional dimensions to the clinical application of exfoliated kidney cells from urine. In this review, we discuss the current evidence regarding the utility of exfoliated proximal tubule cells (PTC), podocytes, mesangial cells, extracellular vesicles and stem/progenitor cells as surrogate markers for the early diagnosis and prognostication of CKD. Future directions for development within this research area are also identified. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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21 pages, 2766 KiB  
Review
Nucleic Acid Nanotechnology for Diagnostics and Therapeutics in Acute Kidney Injury
by Yiwen Ying, Qian Tang, Da Han and Shan Mou
Int. J. Mol. Sci. 2022, 23(6), 3093; https://doi.org/10.3390/ijms23063093 - 13 Mar 2022
Cited by 2 | Viewed by 3004
Abstract
Acute kidney injury (AKI) has impacted a heavy burden on global healthcare system with a high morbidity and mortality in both hospitalized and critically ill patients. However, there are still some shortcomings in clinical approaches for the disease to date, appealing for an [...] Read more.
Acute kidney injury (AKI) has impacted a heavy burden on global healthcare system with a high morbidity and mortality in both hospitalized and critically ill patients. However, there are still some shortcomings in clinical approaches for the disease to date, appealing for an earlier recognition and specific intervention to improve long-term outcomes. In the past decades, owing to the predictable base-pairing rule and highly modifiable characteristics, nucleic acids have already become significant biomaterials for nanostructure and nanodevice fabrication, which is known as nucleic acid nanotechnology. In particular, its excellent programmability and biocompatibility have further promoted its intersection with medical challenges. Lately, there have been an influx of research connecting nucleic acid nanotechnology with the clinical needs for renal diseases, especially AKI. In this review, we begin with the diagnostics of AKI based on nucleic acid nanotechnology with a highlight on aptamer- and probe-functionalized detection. Then, recently developed nanoscale nucleic acid therapeutics towards AKI will be fully elucidated. Furthermore, the strengths and limitations will be summarized, envisioning a wiser and wider application of nucleic acid nanotechnology in the future of AKI. Full article
(This article belongs to the Special Issue Cellular and Molecular Research of Kidney Diseases)
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