Artículo del mes
mayo 2021

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

Referencia artículo:
Miguel V, Tituaña J, Herrero JI, Herrero L, Serra D, Cuevas P, Barbas C, Puyol DR, Márquez-Expósito L, Ruiz-Ortega M, Castillo C, Sheng X, Susztak K, Ruiz-Canela M, Salas-Salvadó J, González MAM, Ortega S, Ramos R, Lamas S. Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. J Clin Invest. 2021 Mar 1;131(5):e140695. PMID: 33465052; PMCID: PMC7919728
En este trabajo hemos estudiado cómo la mejora de la capacidad energética de las células epiteliales tubulares renales protege al riñón de la fibrosis. Mediante la sobre-expresión de una proteína enzimática mitocondrial, Cpt1a, que permite que los ácidos grasos de cadena larga puedan entrar en las mitocondrias, hemos observado en diferentes modelos experimentales de fibrosis, que existe una protección significativa frente al desarrollo de fibrosis. El metabolismo de los ácidos grasos dentro de la mitocondria confiere un gran poder bioenergético, al generar una gran cantidad de ATP y mantener a las células epiteliales en un estado óptimo para defenderse de la inflamación crónica, origen principal de la fibrosis.
Resumen
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.
Sobre el grupo investigador