MiR-9-5p protects from kidney fibrosis by metabolic reprogramming

Abstract

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and control biological processes, including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-{beta}1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA sequencing (RNA-Seq) studies in the UUO model revealed that this protection was mediated by a global shift in the expression profile of genes related to key metabolic pathways, including mitochondrial dysfunction, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glycolysis, preventing their UUO-dependent down-regulation. This effect was mirrored by a prevention in the TGF-{beta}1-induced bioenergetics changes in HKC-8 cells. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1)-peroxisome proliferator-activated receptor alpha (PPAR) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.