MicroRNA-214 Antagonism Protects against Renal Fibrosis

Abstract

Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-b signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-b blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-b signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Specific expression of miRNAs during kidney disease could serve as a potential diagnostic approach [see below and (336)]. Genetic deletion or treatment with antagonists in renal fibrosis showed that miR-21 (337), miR-214 (338), and miR-192 (339) are profibrotic whereas the miR-29 family (340), miR-200b (341), and miR-30e (342) are anti-fibrotic. Most of the miRs were suggested to target TGF-b signaling, collagen expression or metabolic pathways.…”

Role of Smad signaling in kidney disease

“…In renal cell carcinoma, miR-629, miR-192, miR-194 and miR-215 that are known to suppress tumor progression are significantly downregulated [117,118]. In diseased human kidney tissue, miR-214 was detected in the glomerulus and tubules and infiltrating immune cells and induced antifibrotic effects independent of Smad2 and Smad3 [119]. In a recent study, miRNA let-7 family members (let-7b/c/ d/g/i) were found to downregulate TGF-β-induced Smad, Col1A2 and Col4A1 expression, which is a key feature of diabetic nephropathy [120].…”

Anti-fibrotic Role of miR-214 in Thioacetamide-induced Liver Cirrhosis in Rats

“…Recent studies have reported differing roles of miR-214 in fibrosis: 3 in the kidney (Zarjou et al 2011;Denby et al 2011Denby et al , 2014, 1 in the liver (Chen et al 2014), and 1 in the heart (Aurora et al 2012). However, the pathophysiological roles of miR-214 in liver fibrosis remain largely unknown.…”