Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis
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. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-offunction (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyltransferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. 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 ; Ministerio de Economia y Competitividad (MINECO) SAF2012-31388 (SL), SAF2015-66107-R (SL), PID2019-104233RB-100 (SL), PI17/01513 (DRP), SAF2017-83813-C3-1-R (DS and LH), cofunded by the European Regional Development Fund, Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (SL, DRP, and MRO), PI17/00119 (MRO), FIS PI17/00625 (DRP), Comunidad de Madrid "NOVELREN" B2017/BMD-3751 (SL, DRP, and MRO)"; Spanish Society of Nephrology (Fundacion Senefro 2017) (SL) and Fundacion Renal "Iñigo Alvarez de Toledo" (SL), the Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y la Nutricion (CIBEROBN) CB06/03/0001 (DS), the Government of Catalonia 2017SGR278 (DS), and the Fundacio La Marato de TV3 201627-30 (DS), all from Spain. The CBMSO receives institutional support from Fundacion "Ramon Areces."