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

Abstract

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and controlbiological processes (BPs), 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-β1)-dependent dedifferentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-β1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) 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-1α, 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 | 411 FIERRO-FERNÁNDEZ Et al.

Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

“…Moreover, in vitro experiments with NRK‐49F cells show that the inhibition of the glycolytic pathway decreased their proliferation rate and the expression of fibronectin and alpha ‐smooth muscle actin (α‐SMA) 54,55 . In the same way, in an in vivo UUO model with overexpression of miR‐9‐5p, which regulates glycolysis, macrophage infiltration is reduced by glycolytic pathway inhibition 54–56 . Likewise, glycolytic pathway inhibition in vivo and in vitro increases podocyte proliferation and differentiation, while decreasing apoptosis and fibronectin expression in tubular epithelial cells 55,57 .…”

“…In the case of the UUO model, the participation of mitochondria in the progression of the illness is less understood, partly because the information in the literature is still scarce and fragmented, but also due to the lack of temporal studies on mitochondrial bioenergetics. However, the information that is currently available clearly shows the prevalence of energy metabolism alterations in UUO‐OKs ever since the early hours of the obstruction, 18,26,33,51,52 which are associated to the decrease in oxidative metabolism in mitochondria, as well as to the increase in anaerobic metabolism and lipid synthesis, and the formation of lipid droplets within the cell 24,33,49,51,52,54–56 . It has been proposed that this early metabolic reprogramming occurs as a result of mitochondrial FA β‐oxidation impairment 33,51,52 .…”

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

“…Finally, miRNAs targeting fibrosis-associated genes (like miR21 or miR9) were protective by inducing metabolic reprograming mainly through modulation of mitochondrial-damage related genes [141,142].…”

Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

“…Interestingly, in miR-21 knockout mice, renal damage was ameliorated, but most of the genes silenced after renal injury were involved in metabolic and mitochondrial functions, with peroxisome proliferator activated receptor-α (PPARα) being a direct target of miR-21 [110,112]. Other recent studies have described that miR-9 and miR-33 regulate metabolic pathways related to fatty acid oxidation, exerting protective effects in experimental renal damage [113,114]. Future preclinical studies are warranted for evaluating potential miRNAs as therapeutic targets.…”