The program of renal fibrogenesis is controlled by microRNAs regulating oxidative metabolism
| العنوان: | The program of renal fibrogenesis is controlled by microRNAs regulating oxidative metabolism |
|---|---|
| المؤلفون: | Diego Rodríguez-Puyol, Laura García-Bermejo, Ricardo Luiz Ramos, Santiago Lamas, Verónica Miguel |
| المساهمون: | 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 |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname Redox Biology Redox Biology, Vol 40, Iss, Pp 101851-(2021) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25f21a82192fc7b9a84acd0c9fd1b1d9Test http://hdl.handle.net/10261/270587Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....25f21a82192fc7b9a84acd0c9fd1b1d9 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |