The program of renal fibrogenesis is controlled by microRNAs regulating oxidative metabolism
| Autor: | Diego Rodríguez-Puyol, Laura García-Bermejo, Ricardo Luiz Ramos, Santiago Lamas, Verónica Miguel |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Sociedad Española de Nefrología, Fundación Renal Íñigo Álvarez de Toledo, Fundación Ramón Areces |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MMP mitochondrial membrane potential Clinical Biochemistry Eto etomoxir Mitochondrion Kidney Biochemistry CPT1A 0302 clinical medicine Fibrosis OCR oxygen consumption rate Beta oxidation lcsh:QH301-705.5 lcsh:R5-920 TFAM mitochondrial transcription factor A Extracellular matrix ECM extracellular matrix Mitochondria medicine.anatomical_structure Fatty acid oxidation lcsh:Medicine (General) Myofibroblast Research Paper Ureteral Obstruction ITS insulin-transferrin-selenium FDR false discovery rate Fatty acid oxidation Extracellular matrix ETC electron transport chain Biology AKI acute kidney injury SPF specific pathogen free Nephropathy Transforming Growth Factor beta1 03 medical and health sciences MicroRNAS Kidney fibrosis FBS fetal bovine serum TGF-β transforming growth factor-β medicine Renal fibrosis miRNAs microRNAs Humans UUO unilateral ureteral obstruction ECAR extracellular acidification rate Organic Chemistry CKD chronic kidney disease TFAM medicine.disease Oxidative Stress 030104 developmental biology lcsh:Biology (General) Cancer research FAN folic acid nephropathy 030217 neurology & neurosurgery FAO fatty acid oxidation EMT epithelial-to-mesenchymal transition |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Redox Biology Redox Biology, Vol 40, Iss, Pp 101851-(2021) |
| Popis: | Excessive accumulation of extracellular matrix (ECM) is the hallmark of fibrotic diseases. In the kidney, it is the final common pathway of prevalent diseases, leading to chronic renal failure. While cytokines such as TGF-β play a fundamental role in myofibroblast transformation, recent work has shown that mitochondrial dysfunction and defective fatty acid oxidation (FAO), which compromise the main source of energy for renal tubular epithelial cells, have been proposed to be fundamental contributors to the development and progression of kidney fibrosis. MicroRNAs (miRNAs), which regulate gene expression post-transcriptionally, have been reported to control renal fibrogenesis. To identify miRNAs involved in the metabolic derangement of renal fibrosis, we performed a miRNA array screen in the mouse model of unilateral ureteral obstruction (UUO). MiR-150-5p and miR-495-3p were selected for their link to human pathology, their role in mitochondrial metabolism and their targeting of the fatty acid shuttling enzyme CPT1A. We found a 2- and 4-fold upregulation of miR-150-5p and miR-495-5p, respectively, in both the UUO and the folic acid induced nephropathy (FAN) models, while TGF-β1 upregulated their expressions in the human renal tubular epithelial cell line HKC-8. These miRNAs synergized with TGF-β regarding its pro-fibrotic effect by enhancing the fibrosis-associated markers Acta2, Col1α1 and Fn1. Bioenergetics studies showed a reduction of FAO-associated oxygen consumption rate (OCR) in HKC-8 cells in the presence of both miRNAs. Consistently, expression levels of their mitochondrial-related target genes CPT1A, PGC1α and the mitochondrial transcription factor A (TFAM), were reduced by half in renal epithelial cells exposed to these miRNAs. By contrast, we did not detect changes in mitochondrial mass and transmembrane potential (ΔѰm) or mitochondrial superoxide radical anion production. Our data support that miR-150 and miR-495 may contribute to renal fibrogenesis by aggravating the metabolic failure critically involved in tubular epithelial cells, ultimately leading to fibrosis. Graphical abstract MiR-150-5p and miR-495-3p exert pro-fibrotic effects by synergizing with TGF-β in the fibrotic response and contributing to the mitochondrial impairment associated to renal fibrosis.Image 1 Highlights • MiR-150-5p and miR-495-3p were upregulated both in the UUO and FAN models. • MiR-150-5p and miR-495-3p synergized with TGF-β profibrotic effects and reduced FAO-associated OCR in renal epithelial cells. • MiR-150-5p and miR-495-3p did not alter mitochondrial transmembrane potential and superoxide radical anion production. • MiRNAs 150-5p and 495-3p are contributors to the metabolic impairment leading to renal fibrosis. |
| Databáze: | OpenAIRE |
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