MicroRNA-214 antagonism protects against renal fibrosis

Laura Denby, Vasudev Ramdas, Ruifang Lu, Bryan R. Conway, Jennifer S. Grant, Brent Dickinson, Arin B. Aurora, John D. McClure, David Kipgen, Christian Delles, Eva Van Rooij, Andrew H. Baker

Research output: Contribution to journalArticle

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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 itsmanipulation remain unknown.We assessed the effect of inhibitingmiR-214 in an animalmodel of renal fibrosis. Inmice, genetic deletion ofmiR-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.WhereasmiR-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.

Original languageEnglish (US)
Pages (from-to)65-80
Number of pages16
JournalJournal of the American Society of Nephrology
Volume25
Issue number1
DOIs
StatePublished - Jan 2014

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MicroRNAs
Fibrosis
Kidney
Ureteral Obstruction
Wounds and Injuries
Microarray Analysis

ASJC Scopus subject areas

  • Nephrology

Cite this

Denby, L., Ramdas, V., Lu, R., Conway, B. R., Grant, J. S., Dickinson, B., ... Baker, A. H. (2014). MicroRNA-214 antagonism protects against renal fibrosis. Journal of the American Society of Nephrology, 25(1), 65-80. https://doi.org/10.1681/ASN.2013010072

MicroRNA-214 antagonism protects against renal fibrosis. / 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.

In: Journal of the American Society of Nephrology, Vol. 25, No. 1, 01.2014, p. 65-80.

Research output: Contribution to journalArticle

Denby, L, Ramdas, V, Lu, R, Conway, BR, Grant, JS, Dickinson, B, Aurora, AB, McClure, JD, Kipgen, D, Delles, C, Van Rooij, E & Baker, AH 2014, 'MicroRNA-214 antagonism protects against renal fibrosis', Journal of the American Society of Nephrology, vol. 25, no. 1, pp. 65-80. https://doi.org/10.1681/ASN.2013010072
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. / MicroRNA-214 antagonism protects against renal fibrosis. In: Journal of the American Society of Nephrology. 2014 ; Vol. 25, No. 1. pp. 65-80.
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