MicroRNA-214 antagonism protects against renal fibrosis

Denby, L. et al. (2014) MicroRNA-214 antagonism protects against renal fibrosis. Journal of the American Society of Nephrology, 25(1), pp. 65-80. (doi: 10.1681/ASN.2013010072) (PMID:24158985) (PMCID:PMC3871772)

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Publisher's URL: http://dx.doi.org/10.1681/ASN.2013010072

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew and Denby, Dr Laura and Lu, Dr Ruifang and Delles, Professor Christian and McClure, Dr John
Authors: Denby, L., Ramdas, V., Lu, R., Conway, B. R., Grant, J. S., Dickinson, B., Aurora, A. B., McClure, J. D., Kipgen, D., Delles, C., van Rooij, E., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
ISSN:1046-6673
ISSN (Online):1943-8052
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
418441Capacity Building Award in Integrative Mammalian BiologyMargaret MacleanBiotechnology and Biological Sciences Research Council (BBSRC)BB/E527071/1RI CARDIOVASCULAR & MEDICAL SCIENCES
519431Interrogation and manipulation of miRNA in acute vascular injuryAndrew BakerBritish Heart Foundation (BHF)RG/09/005/27915RI CARDIOVASCULAR & MEDICAL SCIENCES