MicroRNA-214 antagonism protects against renal fibrosis

TY - JOUR

T1 - MicroRNA-214 antagonism protects against renal fibrosis

AU - Denby, Laura

AU - Ramdas, Vasudev

AU - Lu, Ruifang

AU - Conway, Bryan R

AU - Grant, Jennifer S

AU - Dickinson, Brent

AU - Aurora, Arin B

AU - McClure, John D

AU - Kipgen, David

AU - Delles, Christian

AU - van Rooij, Eva

AU - Baker, Andrew H

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - Animals

KW - Disease Models, Animal

KW - Fibrosis

KW - Gene Deletion

KW - Gene Expression

KW - Humans

KW - Imidazoles

KW - Kidney

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - MicroRNAs

KW - Quinoxalines

KW - Renal Insufficiency, Chronic

KW - Signal Transduction

KW - Smad2 Protein

KW - Smad3 Protein

KW - Transforming Growth Factor beta

KW - Ureteral Obstruction

U2 - 10.1681/ASN.2013010072

DO - 10.1681/ASN.2013010072

M3 - Article

C2 - 24158985

SN - 1046-6673

VL - 25

SP - 65

EP - 80

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

IS - 1

ER -