title: 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-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.
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Laura
authors.initials: L
authors.lastname: Denby
authors.forename: Vasudev
authors.initials: V
authors.lastname: Ramdas
authors.forename: Ruifang
authors.initials: R
authors.lastname: Lu
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Grant
authors.forename: Brent
authors.initials: B
authors.lastname: Dickinson
authors.forename: Arin B
authors.initials: AB
authors.lastname: Aurora
authors.forename: John D
authors.initials: JD
authors.lastname: McClure
authors.forename: David
authors.initials: D
authors.lastname: Kipgen
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011810:Quinoxalines / Q000494:pharmacology; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000037:antagonists & inhibitors; D051900:Smad3 Protein / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014517:Ureteral Obstruction / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D007093:Imidazoles; C531950:MIRN21 microRNA, mouse; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; C534781:Mirn214 microRNA, mouse; D011810:Quinoxalines; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta