Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis
Year: 2021
Type: article
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 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.
DOI: 10.1172/jci140695
Authors: Verónica Miguel, Jessica Tituaña, J.Ignacio Herrero, Laura Herrero, Dolors Serra, Paula Cuevas, Coral Barbas, Diego Rodríguez Puyol, Laura Márquez-Expósito, Marta Ruiz-Ortega, Carolina Castillo, Xin Sheng, Katalin Susztak, Miguel Ruiz-Canela, Jordi Salas-Salvadó, Miguel A. Martínez González, Sagrario Ortega, Ricardo Ramos, Santiago Lamas
Institutions: Consejo Superior de Investigaciones Científicas, Centro de Biología Molecular Severo Ochoa, Instituto de Salud Carlos III, Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Centro de Investigación Biomédica en Red, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Universidad San Pablo CEU, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Hospital Universitario Príncipe de Asturias, University of Pennsylvania, Navarre Institute of Health Research, Universidad de Navarra, Institut de Recerca Biomèdica Catalunya Sud, Universitat Rovira i Virgili, Spanish National Cancer Research Centre
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Gladstone Institutes, Fundació la Marató de TV3, Comunidad de Madrid, Sociedad Española de Nefrología, Centro de Biología Molecular Severo Ochoa, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Fundación Mapfre, Generalitat Valenciana, Ministerio de Ciencia e Innovación, Centro Nacional de Investigaciones Cardiovasculares, Junta de Andalucía, Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición, Universidade de Santiago de Compostela, Gobierno de Navarra, National Institutes of Health, Medical Research Council, Consejo Superior de Investigaciones Científicas, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G100543663, G1240442146, G1279912698, G1372021016, G1389033685, G1442347428, G1469509158, G1553903662, G1617498335, PREDIMED-PLUS: efecto de una dieta mediterránea hipocalórica y promoción de la actividad física en prevención primaria cardiovascular. Estudio piloto sobre marcadores intermedios, G1661252406, G1721971985, G1750484739, G1881394406, G1916957000, G1940426220, G1982901712, Dietary Interventions, Metabolites, and Type 2 Diabetes, Epigenetics of Chronic Kidney Disease, G2389799761, G2444455660, G2562317630, G2619058490, G2620658983, G2647692628, G2673512141, G2680516326, G2684494655, G2687621885, G2703367647, G2725398547, G2860824219, G2932827979, G3022609761, G3059837661, G3157944966, G3184222797, G3205439833, G3234084033, Kinasa ligada a integrinas: posible biomarcador de progresión de la enfermedad renal crónica (ERC) y modulador de la disfunción monocitaria responsable del daño cardiovascular, G3433371377, G346601977, G3650381748, G3688119456, G3805444271, G4162932109, G4282990219, G4398814152, G4437166959, G4487147551, G4494103574, G4587032617, G4662533551, G4786509053, G5226096627, APOL1 associated disease spectrum, G5542193060, G5644734788, G5799734990, G5856188278, G5919349966, G5929557949, G6109029077, G620079848, G6558908843, G669311712, G6695954693, G6772016530, G6889597758, G6902420817, G6927480760, G721827567, G7427883014, G7931495324, Dietary Interventions, Metabolites, and Risk of Type 2 Diabetes, G8289360861, G831563074, G8485926315, G867847296, G880079747, G8895148634, The role of cytosolic nucleotide sensors in inflammatory fibrosis, Adaptive and maladaptive repair after kidney injury, Mediterranean diet, Metabolites, and Cardiovascular Disease, G91606131
OpenAlex ID: W3122688842