MiR-9-5p protects from kidney fibrosis by metabolic reprogramming
| Autor: | Carolina Castillo, Laura Marquez-Exposito, Cristina Nuevo-Tapioles, Verónica Miguel, María Monsalve, Santiago Lamas, Jessica Tituaña, Pablo Cannata, Marta Fierro-Fernández, J. Ignacio Herrero, Eva Blanco‐Ruiz, Marta Ruiz-Ortega, Ricardo Alan Verdú Ramos |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundación Renal Íñigo Álvarez de Toledo, Instituto de Salud Carlos III, Fundación Ramón Areces, European Commission, Comunidad de Madrid |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male 030232 urology & nephrology Oxidative phosphorylation Mitochondrion Biochemistry Transforming Growth Factor beta1 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Fibrosis microRNA Coactivator Gene expression Genetics Renal fibrosis Animals Humans Medicine Glycolysis Receptor Molecular Biology 030304 developmental biology Mice Knockout 0303 health sciences urogenital system business.industry medicine.disease Cellular Reprogramming Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha 3. Good health Mice Inbred C57BL MicroRNAs 030104 developmental biology Gene Expression Regulation Cancer research Kidney Diseases Transcriptome business Reprogramming 030217 neurology & neurosurgery Biotechnology Ureteral Obstruction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname bioRxiv |
| DOI: | 10.1101/667972 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|