Author, as appears in the article.: Miguel, Veronica; Tituana, Jessica; Ignacio Herrero, J.; Herrero, Laura; Serra, Dolors; Cuevas, Paula; Barbas, Coral; Rodriguez Puyol, Diego; Marquez-Exposito, Laura; Ruiz-Ortega, Marta; Castillo, Carolina; Sheng, Xin; Susztak, Katalin; Ruiz-Canela, Miguel; Salas-Salvado, Jordi; Martinez Gonzalez, Miguel A.; Ortega, Sagrario; Ramos, Ricardo; Lamas, Santiago;
Department: Bioquímica i Biotecnologia
URV's Author/s: Salas Salvadó, Jorge
Keywords: Ureter obstruction Unclassified drug Transgenic mouse Renal insufficiency, chronic Priority journal Population Pluripotent Pathology Palmitic acid Oxygen consumption rate Oxidation Nonhuman Nephrotoxicity Mouse Mitochondrion Mice, transgenic Mice, knockout Mice Metabolism Macrophage Liver Knockout mouse Kidney tubules Kidney tubule Kidney function Kidney fibrosis Kidney disease Immunofluorescence Homeostasis Genetics Gene overexpression Gene nomenclature Gene expression regulation, enzymologic Gene expression regulation Folic acid Flow cytometry Fibrosis Fatty-acid oxidation Fatty acids Fatty acid oxidation Fatty acid Expression Experimental renal fibrosis Epithelium cell Epithelial-cells Enzymology Disease models, animal Disease model Disease Cpt1b protein, mouse Controlled study Chronic kidney failure Cell damage Carnitine palmitoyltransferase Carnitine palmitoyl transferase 1a Carnitine o-palmitoyltransferase Biosynthesis Bioenergy Beta-oxidation Article Animals Animal model Animal experiment Animal cell Animal Aerobic metabolism Adenosine triphosphate Adenine Acylcarnitine
Abstract: Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present 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 whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of shortand 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.
Thematic Areas: Saúde coletiva Odontología Medicine, research & experimental Medicine (miscellaneous) Medicine (all) Medicina veterinaria Medicina ii Medicina i Interdisciplinar General medicine Farmacia Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Biotecnología
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: jordi.salas@urv.cat
Author identifier: 0000-0003-2700-7459
Record's date: 2023-02-19
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.jci.org/articles/view/140695/pdf
Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Journal Of Clinical Investigation. 131 (5):
APA: Miguel, Veronica; Tituana, Jessica; Ignacio Herrero, J.; Herrero, Laura; Serra, Dolors; Cuevas, Paula; Barbas, Coral; Rodriguez Puyol, Diego; Marquez- (2021). Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. Journal Of Clinical Investigation, 131(5), -. DOI: 10.1172/JCI140695
Article's DOI: 10.1172/JCI140695
Entity: Universitat Rovira i Virgili
Journal publication year: 2021
Publication Type: Journal Publications
Repositori URV