MicroRNA-214 Antagonism Protects against Renal Fibrosis : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Denby, Laura*; Ramdas, Vasudev*; Lu, Ruifang*; Conway, Bryan R.†; Grant, Jennifer S.*; Dickinson, Brent‡; Aurora, Arin B.§; McClure, John D.*; Kipgen, David‖; Delles, Christian*; van Rooij, Eva‡; Baker, Andrew H.*

*BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;

†Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;

‡miRagen Therapeutics, Boulder, Colorado;

§Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas; and

‖Department of Pathology, Southern General Hospital, Glasgow, United Kingdom

Correspondence: Dr. Laura Denby or Prof. Andrew H. Baker, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TA, United Kingdom. Email: [email protected] or [email protected]

Received January 18, 2013

Accepted June 28, 2013

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-β 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-β 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-β signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.