Articles producció científica> Bioquímica i Biotecnologia

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

  • Identification data

    Identifier: imarina:9177882
    Authors:
    Miguel, VeronicaTituana, JessicaIgnacio Herrero, JHerrero, LauraSerra, DolorsCuevas, PaulaBarbas, CoralRodriguez Puyol, DiegoMarquez-Exposito, LauraRuiz-Ortega, MartaCastillo, CarolinaSheng, XinSusztak, KatalinRuiz-Canela, MiguelSalas-Salvado, JordiMartinez Gonzalez, Miguel AOrtega, SagrarioRamos, RicardoLamas, Santiago
    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.
  • Others:

    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: 2024-11-09
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://www.jci.org/articles/view/140695/pdf
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Journal Of Clinical Investigation. 131 (5): e140695-
    APA: Miguel, Veronica; Tituana, Jessica; Ignacio Herrero, J; Herrero, Laura; Serra, Dolors; Cuevas, Paula; Barbas, Coral; Rodriguez Puyol, Diego; Marquez-E (2021). Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. Journal Of Clinical Investigation, 131(5), e140695-. DOI: 10.1172/JCI140695
    Article's DOI: 10.1172/JCI140695
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2021
    Publication Type: Journal Publications
  • Keywords:

    Medicine (Miscellaneous),Medicine, Research & Experimental
    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
    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
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