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

Identificador:  imarina:9177882

Handle: https://hdl.handle.net/20.500.11797/imarina9177882

Autores:  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

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 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.