Suchergebnisse

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological 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 de‐differentiation 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 reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells. ; This work was supported by Grants from the Ministerio de Economía y Competitividad (MINECO) SAF 2012‐31388 (SL) and SAF2015‐66107‐R (SL), both cofunded by the European Regional Development Fund, Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (SL and MRO), PI17/00119 (MRO), SAF2015‐63904‐R (MM), cofunded by the European Regional Development Fund, European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement 721236‐TREATMENT (MM), Comunidad de Madrid "NOVELREN" B2017/BMD­3751 (SL and MRO), and Fundación Renal "Iñigo Alvarez de Toledo" (SL), all from Spain. The CBMSO receives institutional support from Fundación "Ramón Areces". VM and CNT were supported by predoctoral fellowships of the FPI Program (BES‐2013‐065986 and BES‐2014‐068929) from MINECO. ; Peer reviewed

Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-offunction (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyltransferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD ; Ministerio de Economia y Competitividad (MINECO) SAF2012-31388 (SL), SAF2015-66107-R (SL), PID2019-104233RB-100 (SL), PI17/01513 (DRP), SAF2017-83813-C3-1-R (DS and LH), cofunded by the European Regional Development Fund, Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (SL, DRP, and MRO), PI17/00119 (MRO), FIS PI17/00625 (DRP), Comunidad de Madrid "NOVELREN" B2017/BMD-3751 (SL, DRP, and MRO)"; Spanish Society of Nephrology (Fundacion Senefro 2017) (SL) and Fundacion Renal "Iñigo Alvarez de Toledo" (SL), the Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y la Nutricion (CIBEROBN) CB06/03/0001 (DS), the Government of Catalonia 2017SGR278 (DS), and the Fundacio La Marato de TV3 201627-30 (DS), all from Spain. The CBMSO receives institutional support from Fundacion "Ramon Areces."