MicroRNA-214 antagonism protects against renal fibrosis
Background: Renal tubulointerstitial fibrosis is a key pathological endpoint in progressive renal disease. Both microRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the specific role of miR-214 in this context, as well as the effects of its inhibition, remain unclear. This study aimed to evaluate the impact of inhibiting miR-214 in an animal model of renal fibrosis.
Methods and Results: In mice, genetic deletion of miR-214 significantly reduced interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Administration of an anti-miR-214 oligonucleotide (anti-miR-214) before UUO in wild-type mice produced similar antifibrotic effects. Biodistribution studies revealed that anti-miR-214 accumulated most prominently in the kidney. Importantly, inhibition of canonical TGF-β signaling did not affect the regulation of miR-214 or miR-21, suggesting that miR-214’s effects are independent of TGF-β signaling. While miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, indicating that miR-214 exerts antifibrotic effects through a Smad 2/3-independent mechanism. Furthermore, combining TGF-β blockade with miR-214 deletion provided additional renal protection. Microarray analysis revealed that miR-214 depletion broadly modulated the transcriptional response to injury. In human kidney tissue, miR-214 was detected in glomerular and tubular cells as well as in infiltrating immune cells within diseased tissue.
Conclusion: Our findings demonstrate that miR-214 promotes fibrosis in renal injury independently of TGF-β signaling. Targeting miR-214 may offer a novel therapeutic strategy Aurora A Inhibitor I for preventing or treating renal fibrosis.