Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

Abstract

It has been reported that transforming growth factor-β1 (TGF-β1) signaling plays an important role in the development of diabetic nephropathy (DN). The nuclear transcription co-repressor Ski-related novel protein N (SnoN) is a critical negative regulator of TGF-β1/Smad signal pathway, involving in tubule epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and tubulointerstitial fibrosis. In this study, we focused on miR-23a as a regulator of SnoN. Our purpose is to study the effects of miR-23a on high glucose (HG)-induced EMT process and ECM deposition in HK2 cells. We found that miR-23a was up-regulated in renal tissues of diabetic patients and HG-induced HK2 cells. Besides, the high level of miR-23a was closely associated with decreased SnoN expression. Knockdown of miR-23a increased SnoN expression and in turn suppressed HG-induced EMT and renal fibrogenesis. Introduction of miR-23a decreased SnoN expression and enhanced the profibrogenic effects of HG on HK2 cells. Next, bioinformatics analysis predicted that the SnoN was a potential target gene of miR-23a. Luciferase reporter assay demonstrated that miR-23a could directly target SnoN. We demonstrated that overexpression of SnoN was sufficient to inhibit HG-induced EMT and renal fibrogenesis in HK2 cells. Furthermore, down-regulation of SnoN partially reversed the protective effect of miR-23a knockdown on HG-induced EMT and renal fibrogenesis in HK2 cells. Collectively, miR-23a and SnoN significantly impact on the progression of HG-induced EMT and renal fibrogenesis in vitro, and they may represent novel targets for the prevention strategies of renal fibrosis in the context of DN.

Emerging role of miRNAs in renal fibrosis

“…miR-let7b and miR-let7d and fibrogenesis are downregulated by TGF-β1 in NRK52E cells, and miR-let7c is also downregulated in HK2 cells under fibrotic conditions [91]. miR-let7b expression is consistent in different animal model of renal fibrosis [11,92], and decreases in miR-let7a-5p have been observed in UUO model mice, contributing to the excessive deposition of collagen and tissue fibrosis in the kidney [46].…”

“…However, another isomiR of mir-23, miR-23a, seems to have the opposite expression trend. miR-23a was recently found to be upregulated in renal tissues of diabetic patients and HK2 cells treated with HG [46].…”

Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases

“…Liu et al reported that miR-130a-5p prevented angiotensin II-induced podocyte apoptosis by modulating phospholipase A2 receptor (PLA2R) [68]. In spite of these trophic effects, miR-130a-3p has been reported to target SnoN, thereby promoting renal fibrosis via TGF-β1/Smad pathway, similar to miR-23a [69]. Further analysis is still required to conclude the potential effects of miR-130a in renal diseases.…”

Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

“…A high level of miR-23a was also observed in diabetic patients and HG-cultured TECs. It directly targets the nuclear transcription co-repressor Ski-related novel protein N (SnoN) (Tan et al, 2006), a crucial negative regulator to TGFβ/Smad3-mediated signaling pathway, to induce fibrosis in DKD (Xu et al, 2018a). Sirtuin 1 (SIRT1) expression in the nucleus and the cytoplasm has also been shown as a renoprotective regulator by inhibiting TGF-β/Smad-induced fibrosis and downstream hypoxia-inducible factor-1α (HIF-1α).…”