Renal tubule Cpt1a overexpression mitigates 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. Defective fatty acid oxidation (FAO), the main source of energy for TECs, contributes to kidney fibrosis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knockin mice subjected to three different models of renal fibrosis exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage. Mitochondrial number, oxygen consumption and ATP levels were restored after FAO-GOF. 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.