MiR‐101a ameliorates AngII‐mediated hypertensive nephropathy by blockade of TGFβ/Smad3 and NF‐κB signalling in a mouse model of hypertension

Abstract

Primary hypertension (essential hypertension or idiopathic hypertension) is regarded as the most common type of hypertension and affects 95% of hypertensive patients. 1 Primary hypertension is a crucial risk factor of cerebral, cardiac, and renal events. Moreover, hypertensive nephropathy is one of the most lethal complications of primary hypertension. Recently, more and more evidence has shown that high blood pressure may cause tubular cell damage and tubulointerstitial fibrosis. In addition, high blood pressure can also cause podocyte effacement and loss, which subsequently results in glomerular basement membrane denudation and adhesion to Bowman's capsule. 2 MicroRNAs (miRNAs or miRs) are small (about 22 nucleotides) noncoding RNAs which regulate gene expression via inhibiting translation or guiding corresponding target mRNA cleavage. 3 Emerging evidence indicates that many miRNAs are often involved in various Summary Hypertensive nephropathy, clinically characterized by progressive renal fibrosis and inflammation, is a severe complication of hypertension. The objectives of this study were to investigate the roles of miR-101a in relieving angiotensin II (Ang II)-mediated hypertensive nephropathy and uncover the possible underlying mechanisms. A hypertensive mouse model was established via continuous 28-day AngII infusion.Systolic blood pressure (SBP), ratio of urine albumin to creatinine, blood urea nitrogen (BUN), serum creatinine (Scr) and glomerular filtration rate (GFR) were evaluated.Dual luciferase reporter assay was used to explore the target of miR-101a. mRNA levels of miR-101a, TGFβRI, fibrotic markers (Collagen I and α-SMA) and pro-inflammatory cytokines (IL-1β and TNF-α) were determined by real-time PCR. Protein levels of TGFβRI, Collagen I, α-SMA, IL-1β, TNF-α, t-p65, P-p65, t-Smad3, P-Smad3, t-IκBα and P-IκBα were detected by western blot. MiR-101a mimics significantly improved GFR and inhibited AngII-induced increase in the ratio of urine albumin to creatinine, BUN and Scr. MiR-101a mimics partially abolished AngII-induced increase in the mRNA and protein level of fibrotic markers by targeting TGFβRI and inhibiting TGFβ/ Smad3 pathway. Moreover, TGFβRI inhibitor galunisertib inhibited AngII-mediated renal injury in mice with hypertensive nephropathy. Additionally, miR-101a overexpression blocked AngII-induced up-regulation of pro-inflammatory markers via suppressing NF-κB pathway. MiR-101a exhibited protective effects against hypertensive nephropathy via inhibiting TGFβ/Smad3 and NF-κB signalling pathways. K E Y W O R D SAngII, hypertensive nephropathy, miR-101a, NF-κB, TGFβRI

A novel identified circular RNA, circ_0000491, aggravates the extracellular matrix of diabetic nephropathy glomerular mesangial cells through suppressing miR‑101b by targeting TGFβRI

“…fibrosis (37), suggesting that inhibiting TGFβri may be a promising anti-fibrotic therapeutic strategy for DN. These findings are consistent with the current study where it was found that circrna_0000491 knockdown inhibited TGFβ1, TGFβri and pSmad3 protein expression levels (34,36).…”

“…In this pathway, TGF-β1 exerts biological effects through binding to type II β-β receptor and subsequently recruits and activates TGFβRI, then the activated TGFβR1 phosphorylates Smad2/3 ( 33 , 34 ). Previous studies have demonstrated that inhibiting TGFβRI significantly improves various disease, including pulmonary fibrosis ( 35 ), hypertensive nephropathy ( 36 ) and tubulo-interstitial fibrosis ( 37 ), suggesting that inhibiting TGFβRI may be a promising anti-fibrotic therapeutic strategy for DN. These findings are consistent with the current study where it was found that circRNA_0000491 knockdown inhibited TGFβ1, TGFβRI and pSmad3 protein expression levels ( 34 , 36 ).…”

Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis

“…Although the anti-fibrotic properties of galunisertib have not been widely explored, there is an emerging evidence for its therapeutic efficacy in liver fibrosis [26,27]. To date, the only report showing a potential benefit of galunisertib for the treatment of renal fibrosis in vivo is the study by Ding et al [90]. This study demonstrated that co-administration of angiotensin II and galunisertib significantly improved renal function in a murine model of hypertensive nephropathy; however, no fibrosis parameters were evaluated.…”

Fibroblast Growth Factor 21 Attenuates Salt-sensitive Hypertension-induced Nephropathy Through Anti-inflammation and Anti-oxidation Mechanism

“…In addition, it has reported that AMPK activation promotes the entry of nuclear factor erythroid 2-related factor-2 (Nrf2) into the nucleus, up-regulates the expressions of antioxidant factors such as heme oxygenase-1 (HO-1) and NAD (P) H:quinone oxidoreductase (NQO-1), thus exerting the effect of antioxidant stress (Ni, Shen et al, 2019;Yamakage, Tanaka et al, 2020). Notably, the injury of renal tubular epithelial cells induced by releasing of in ammatory mediators and oxidative stress plays a key role in the pathogenesis of hypertensive nephropathy (Ding, Zhou et al, 2019;Zhang, Cheng et al, 2020). Moreover, a study shown that FGF21 prevented type 2 diabetic-induced cardiomyopathy through activation of AMPK-mediated antioxidation and lipid-lowering effects (Yang, Feng et al, 2018).…”