International Journal of Molecular Sciences

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Open AccessEditorial

The Role of Non-Coding RNAs in Kidney Diseases

by Laurent Metzinger, Juan Antonio Moreno and Valérie Metzinger-Le Meuth

Int. J. Mol. Sci. 2022, 23(12), 6624; https://doi.org/10.3390/ijms23126624 - 14 Jun 2022

Cited by 2 | Viewed by 1541

Abstract

Renal diseases include different pathologies, such as acute kidney injury (AKI), chronic kidney disease (CKD), end-stage renal disease (ESRD), diabetic nephropathy (DN), kidney cancer, polycystic kidney disease, etc [...] Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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11 pages, 1215 KiB

Open AccessArticle

Syndecan-1 and Free Indoxyl Sulfate Levels Are Associated with miR-126 in Chronic Kidney Disease

by Ophélie Fourdinier, Griet Glorieux, Benjamin Brigant, Momar Diouf, Anneleen Pletinck, Raymond Vanholder, Gabriel Choukroun, Francis Verbeke, Ziad A. Massy, Valérie Metzinger-Le Meuth, Laurent Metzinger and on behalf of the European Uremic Toxin Work Group-EUTox

Int. J. Mol. Sci. 2021, 22(19), 10549; https://doi.org/10.3390/ijms221910549 - 29 Sep 2021

Cited by 15 | Viewed by 2105

Abstract

Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and [...] Read more.

Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically cel-miR-39. The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD. Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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16 pages, 4783 KiB

Open AccessArticle

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice

by Paola Pontrelli, Francesca Conserva, Rossella Menghini, Michele Rossini, Alessandra Stasi, Chiara Divella, Viviana Casagrande, Claudia Cinefra, Mariagrazia Barozzino, Simona Simone, Francesco Pesce, Giuseppe Castellano, Giovanni Stallone, Anna Gallone, Francesco Giorgino, Massimo Federici and Loreto Gesualdo

Int. J. Mol. Sci. 2021, 22(10), 5194; https://doi.org/10.3390/ijms22105194 - 14 May 2021

Cited by 6 | Viewed by 2878

Abstract

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of [...] Read more.

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16^INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16^INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy. Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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20 pages, 2549 KiB

Open AccessArticle

Increased miR-7641 Levels in Peritoneal Hyalinizing Vasculopathy in Long-Term Peritoneal Dialysis Patients

by Raquel Díaz, Pilar Sandoval, Raul R. Rodrigues-Diez, Gloria del Peso, José A Jiménez-Heffernan, Ricardo Ramos-Ruíz, Carlos Llorens, Gustavo Laham, Mabel Alvarez-Quiroga, Manuel López-Cabrera, Marta Ruiz-Ortega, María A. Bajo and Rafael Selgas

Int. J. Mol. Sci. 2020, 21(16), 5824; https://doi.org/10.3390/ijms21165824 - 13 Aug 2020

Cited by 5 | Viewed by 2786

Abstract

Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. [...] Read more.

Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. Clinical data were collected and lesions were evaluated by immunohistochemistry. In selected biopsies a microRNA (miRNA)-sequencing analysis was performed. Only fifteen patients (15%) showed PHV at different degrees. PHV prevalence was significantly lower among patients using PD fluids containing low glucose degradation products (GDP) (5.9% vs. 24.5%), angiotensin converting enzyme inhibitors (ACEIs) (7.5% vs. 23.4%), statins (6.5% vs. 22.6%) or presenting residual renal function, suggesting the existence of several PHV protective factors. Peritoneal biopsies from PHV samples showed loss of endothelial markers and induction of mesenchymal proteins, associated with collagen IV accumulation and wide reduplication of the basement membrane. Moreover, co-expression of endothelial and mesenchymal markers, as well as TGF-β1/Smad3 signaling activation were found in PHV biopsies. These findings suggest that an endothelial-to-mesenchymal transition (EndMT) process was taking place. Additionally, significantly higher levels of miR-7641 were observed in severe PHV compared to non-PHV peritoneal biopsies. Peritoneal damage by GDPs induce miRNA deregulation and an EndMT process in submesothelial vessels, which could contribute to collagen IV accumulation and PHV. Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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Review

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19 pages, 725 KiB

Open AccessReview

Non-Coding RNAs in Kidney Diseases: The Long and Short of Them

by Juan Antonio Moreno, Eya Hamza, Melania Guerrero-Hue, Sandra Rayego-Mateos, Cristina García-Caballero, Mercedes Vallejo-Mudarra, Laurent Metzinger and Valérie Metzinger-Le Meuth

Int. J. Mol. Sci. 2021, 22(11), 6077; https://doi.org/10.3390/ijms22116077 - 4 Jun 2021

Cited by 19 | Viewed by 4106

Abstract

Recent progress in genomic research has highlighted the genome to be much more transcribed than expected. The formerly so-called junk DNA encodes a miscellaneous group of largely unknown RNA transcripts, which contain the long non-coding RNAs (lncRNAs) family. lncRNAs are instrumental in gene [...] Read more.

Recent progress in genomic research has highlighted the genome to be much more transcribed than expected. The formerly so-called junk DNA encodes a miscellaneous group of largely unknown RNA transcripts, which contain the long non-coding RNAs (lncRNAs) family. lncRNAs are instrumental in gene regulation. Moreover, understanding their biological roles in the physiopathology of many diseases, including renal, is a new challenge. lncRNAs regulate the effects of microRNAs (miRNA) on mRNA expression. Understanding the complex crosstalk between lncRNA–miRNA–mRNA is one of the main challenges of modern molecular biology. This review aims to summarize the role of lncRNA on kidney diseases, the molecular mechanisms involved, and their function as emerging prognostic biomarkers for both acute and chronic kidney diseases. Finally, we will also outline new therapeutic opportunities to diminish renal injury by targeting lncRNA with antisense oligonucleotides. Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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18 pages, 6225 KiB

Open AccessReview

Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease

by Swayam Prakash Srivastava, Julie E. Goodwin, Pratima Tripathi, Keizo Kanasaki and Daisuke Koya

Int. J. Mol. Sci. 2021, 22(11), 6027; https://doi.org/10.3390/ijms22116027 - 2 Jun 2021

Cited by 21 | Viewed by 4184

Abstract

Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression [...] Read more.

Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression of lncRNAs in diabetes and diabetic kidney disease have been reported. LncRNAs regulate diverse targets and can function as sponges for regulatory microRNAs, which influence disease phenotype in the kidneys. Importantly, lncRNAs and microRNAs may regulate bidirectional or crosstalk mechanisms, which need to be further investigated. These studies offer the novel possibility that lncRNAs may be used as potential therapeutic targets for diabetes and diabetic kidney diseases. Here, we discuss the functions and mechanisms of actions of lncRNAs, and their crosstalk interactions with microRNAs, which provide insight and promise as therapeutic targets, emphasizing their role in the pathogenesis of diabetes and diabetic kidney disease Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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19 pages, 1544 KiB

Open AccessReview

Non-Coding RNAs in Hereditary Kidney Disorders

by Julie Xia Zhou and Xiaogang Li

Int. J. Mol. Sci. 2021, 22(6), 3014; https://doi.org/10.3390/ijms22063014 - 16 Mar 2021

Cited by 12 | Viewed by 3826

Abstract

Single-gene defects have been revealed to be the etiologies of many kidney diseases with the recent advances in molecular genetics. Autosomal dominant polycystic kidney disease (ADPKD), as one of the most common inherited kidney diseases, is caused by mutations of PKD1 or PKD2 [...] Read more.

Single-gene defects have been revealed to be the etiologies of many kidney diseases with the recent advances in molecular genetics. Autosomal dominant polycystic kidney disease (ADPKD), as one of the most common inherited kidney diseases, is caused by mutations of PKD1 or PKD2 gene. Due to the complexity of pathophysiology of cyst formation and progression, limited therapeutic options are available. The roles of noncoding RNAs in development and disease have gained widespread attention in recent years. In particular, microRNAs in promoting PKD progression have been highlighted. The dysregulated microRNAs modulate cyst growth through suppressing the expression of PKD genes and regulating cystic renal epithelial cell proliferation, mitochondrial metabolism, apoptosis and autophagy. The antagonists of microRNAs have emerged as potential therapeutic drugs for the treatment of ADPKD. In addition, studies have also focused on microRNAs as potential biomarkers for ADPKD and other common hereditary kidney diseases, including HNF1β-associated kidney disease, Alport syndrome, congenital abnormalities of the kidney and urinary tract (CAKUT), von Hippel–Lindau (VHL) disease, and Fabry disease. This review assembles the current understanding of the non-coding RNAs, including microRNAs and long noncoding RNAs, in polycystic kidney disease and these common monogenic kidney diseases. Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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28 pages, 982 KiB

Open AccessReview

MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application

by Linsey J. F. Peters, Jürgen Floege, Erik A. L. Biessen, Joachim Jankowski and Emiel P. C. van der Vorst

Int. J. Mol. Sci. 2020, 21(18), 6547; https://doi.org/10.3390/ijms21186547 - 7 Sep 2020

Cited by 52 | Viewed by 6065

Abstract

There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after [...] Read more.

There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after kidney damage has occurred. This highlights the need for better mechanistic insight into CKD as well as improved clinical tools for both diagnosis and treatment. In the last decade, many studies have focused on microRNAs (miRs) as novel diagnostic tools or clinical targets. MiRs are small non-coding RNA molecules that are involved in post-transcriptional gene regulation and many have been studied in CKD. A wide array of pre-clinical and clinical studies have highlighted the potential role for miRs in the pathogenesis of hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, kidney tubulointerstitial fibrosis, and some of the associated cardiovascular complications. In this review, we will provide an overview of the miRs studied in CKD, especially highlighting miR-103a-3p, miR-192-5p, the miR-29 family and miR-21-5p as these have the greatest potential to result in novel therapeutic and diagnostic strategies. Full article

(This article belongs to the Special Issue The Role of Non-coding RNAs in Kidney Diseases)

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