Knockdown of LncRNA-H19 Ameliorates Kidney Fibrosis in Diabetic Mice by Suppressing miR-29a-Mediated EndMT.

Sen Shi,Yanzheng He,Li Song,Yong Liu,Hao Yu,Jianhua He,Songlin Feng

doi:10.3389/fphar.2020.586895

Sen Shi, Yanzheng He + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2020.586895

Copy DOI

Abstract

Diabetic nephropathy is the leading cause of kidney fibrosis. Recently, altered expressed or dysfunction of some long non-coding RNAs (lncRNAs) has been linked to kidney fibrosis; however, the mechanisms of lncRNAs in kidney fibrosis remain unclear. We have shown that the DPP-4 inhibitor linagliptin can inhibit endothelial-mesenchymal transition (EndMT) and ameliorate diabetic kidney fibrosis associated with DPP-4 protein levels via the induction of miR-29. Here, we found that expression of the lncRNA H19 was significantly up-regulated in TGF-β2-induced fibrosis in human dermal microvascular endothelial cells (HMVECs) in vitro, and in kidney fibrosis of streptozotocin-induced diabetic CD-1 mice. We also detected up-regulated H19 expression and down-regulated miR-29a expression in the early and advanced mouse models of diabetic kidney fibrosis. H19 knockdown significantly attenuated kidney fibrosis in vitro and in vivo, which was associated with the inhibition of the EndMT-associated gene FSP-1. We also found that the up-regulation of H19 observed in fibrotic kidneys associated with the suppression of miR-29a in diabetic mice. H19, miR-29a, and EndMT contribute to a regulatory network involved in kidney fibrosis, and are associated with regulation of the TGF-β/SMAD3 singling pathway. This study indicates that inhibition of LncRNA H19 represents a novel anti-fibrotic treatment for diabetic kidney diseases.

Highlights

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with both type I and type II diabetes mellitus and is the leading cause of end-stage renal disease worldwide (Loeffler and Wolf, 2015)
We have found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of endothelial-mesenchymal transition (EndMT) and the restoration of microRNA -29s (Kanasaki et al, 2014)
H19 knockdown significantly attenuated kidney fibrosis in vitro and in vivo, which was associated with the inhibition of the EndMT associated FSP-1

Summary

Introduction

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with both type I and type II diabetes mellitus and is the leading cause of end-stage renal disease worldwide (Loeffler and Wolf, 2015). Kidney fibrosis is usually the final outcome of many renal diseases, of which DN is the leading cause (Kanasaki et al, 2013). H19 Protects Against Kidney Fibrosis seryl-aspartyl-lysyl-proline (AcSDKP), the substrate of angiotensin-converting enzyme (ACE), is an orally available peptide drug used to cure kidney fibrosis in diabetic mice. AcSDKP treatment can restore the level of anti fibrosis miRNAs in diabetic mice, such as miR-29s and let-7s (Nitta et al, 2016). DPP-4 inhibitors have been introduced into the market as antidiabetic drugs. We have found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA (miR) -29s (Kanasaki et al, 2014). Whether there are other RNA mechanisms underlying diabetic fibrosis remains largely unclear

Methods

Results

Conclusion