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

TLDR

Chronic kidney disease is a major health challenge, and in its progression renal tubular epithelial cells exhibit persistent inflammation and fibrosis, partly due to reduced fatty acid oxidation that fuels disease pathogenesis. The study aims to test whether enhancing fatty acid oxidation via CPT1A overexpression in tubular cells can protect against kidney fibrosis and to propose FAO‑GOF as a therapeutic strategy. A conditional transgenic mouse overexpressing CPT1A in renal tubular cells was created to enhance fatty acid oxidation. CPT1A overexpression in mice reduced fibrosis, inflammation, and cellular damage across multiple models, restored mitochondrial function and fatty acid oxidation, and similar FAO impairment was observed in human CKD patients.

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 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.