Renal tubule Cpt1a overexpression mitigates kidney fibrosis by restoring mitochondrial homeostasis
Renal tubule Cpt1a overexpression mitigates kidney fibrosis by restoring mitochondrial homeostasis
Abstract Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Defective fatty acid oxidation (FAO), the main source of energy for TECs, contributes to kidney fibrosis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knock-in mice subjected to three different models of renal fibrosis exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage. Mitochondrial number, oxygen consumption and ATP levels were restored after FAO-GOF. Studies in patients evidenced 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.
Barbas Coral、Ruiz-Canela Miguel、Serra Dolors、Mart¨anez Gonzalez Miguel A.、Puyol Diego Rodr¨aguez、Salas-Salvad¨? Jordi、Hu Frank B.、Ortega Sagrario、Lamas Santiago、Ramos Ricardo、Cuevas Paula、Ruiz-Ortega Marta、Susztak Katalin、Herrero J.Ignacio、M¨￠rquez-Exposito Laura、Titua?a Jessica、Castillo Carolina、Miguel Ver¨?nica、Herrero Laura、Sheng Xin
Centre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEUUniversity of Navarra, Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra)||CIBER de Fisiopatolog¨aa de la Obesidad y Nutrici¨?n (CIBEROBN), Instituto de Salud Carlos IIIDepartment of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona||Centro de Investigaci¨?n Biom¨|dica en Red de Fisiopatolog¨aa de la Obesidad y la Nutrici¨?n (CIBEROBN)University of Navarra, Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra)||CIBER de Fisiopatolog¨aa de la Obesidad y Nutrici¨?n (CIBEROBN), Instituto de Salud Carlos III||Department of Nutrition, Harvard T.H. Chan School of Public HealthDepartment of Medicine and Medical Specialties, Research Foundation of the University Hospital ?°Pr¨ancipe de Asturias,?± IRYCIS, Alcal¨￠ UniversityCIBER de Fisiopatolog¨aa de la Obesidad y Nutrici¨?n (CIBEROBN), Instituto de Salud Carlos III||Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Health Research InstituteDepartment of Nutrition, Harvard T.H. Chan School of Public Health||Channing Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical SchoolTransgenics Unit, Spanish National Cancer Research CentreProgramme of Physiological and Pathological ProcessesGenomic Facility, Parque Cient¨afico de MadridCentre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEUCellular and Molecular Biology in Renal and Vascular Pathology Laboratory. Fundaci¨?n Instituto de Investigaci¨?n Sanitaria-Fundaci¨?n Jim¨|nez D¨aaz-Universidad Aut¨?noma MadridDivision of Nephrology, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of PennsylvaniaProgramme of Physiological and Pathological ProcessesCellular and Molecular Biology in Renal and Vascular Pathology Laboratory. Fundaci¨?n Instituto de Investigaci¨?n Sanitaria-Fundaci¨?n Jim¨|nez D¨aaz-Universidad Aut¨?noma MadridProgramme of Physiological and Pathological ProcessesUniversity Hospital ?°Pr¨ancipe de AsturiasProgramme of Physiological and Pathological ProcessesDepartment of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona||Centro de Investigaci¨?n Biom¨|dica en Red de Fisiopatolog¨aa de la Obesidad y la Nutrici¨?n (CIBEROBN)Division of Nephrology, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania
基础医学生理学生物化学
Barbas Coral,Ruiz-Canela Miguel,Serra Dolors,Mart¨anez Gonzalez Miguel A.,Puyol Diego Rodr¨aguez,Salas-Salvad¨? Jordi,Hu Frank B.,Ortega Sagrario,Lamas Santiago,Ramos Ricardo,Cuevas Paula,Ruiz-Ortega Marta,Susztak Katalin,Herrero J.Ignacio,M¨￠rquez-Exposito Laura,Titua?a Jessica,Castillo Carolina,Miguel Ver¨?nica,Herrero Laura,Sheng Xin.Renal tubule Cpt1a overexpression mitigates kidney fibrosis by restoring mitochondrial homeostasis[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2020.02.18.952440.点此复制
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