Chronic kidney disease (CKD) affects millions worldwide, with renal fibrosis representing a final common pathway of chronic renal injury. Defective fatty acid oxidation (FAO) in renal tubular epithelial cells has been shown to promote kidney fibrosis, but whether FAO impairment in kidney vascular endothelial cells contributes to renal pathology has remained unclear.
A new study published in Life Metabolism by Prof. Jianhua Xiong and colleagues at Emory University reports that endothelial-specific loss of CPT2, a key component of mitochondrial long-chain FAO, reduces acetyl-CoA availability, activates an endothelial-to-mesenchymal transition (EndoMT)-like program, and promotes renal injury and fibrotic remodeling.
Using VE-cadherin-Cre-driven endothelial Cpt2 knockout mice (Cpt2^E-KO), the researchers found that endothelial CPT2 loss did not impair viability or lower ATP levels, consistent with the predominantly glycolytic metabolism of quiescent endothelium. However, Cpt2-deficient endothelial cells failed to increase oxygen consumption in response to palmitate, indicating impaired long-chain fatty acid oxidation. These cells also showed upregulation of mesenchymal-associated markers (Cd44, Cdh2, and Zeb2), and this phenotype was suppressed by heterologous CPT2 expression.
Mechanistically, long-chain FAO contributes to the generation of acetyl-CoA, a central metabolite and acetyl-group donor for protein acetylation. Cpt2^E-KO endothelial cells exhibited reduced acetyl-CoA levels, while acetate supplementation, which can replenish acetyl-CoA through ACSS2, partially suppressed EndoMT-associated gene expression. These findings suggest that FAO-derived acetyl-CoA helps restrain EndoMT-like endothelial plasticity.
In Cpt2^E-KO mice, the researchers observed elevated kidney injury molecule-1 (KIM-1) and increased collagen deposition by Masson's trichrome staining, supporting an association between endothelial CPT2 loss and renal injury and fibrotic remodeling. In 10- to 14-month-old animals, mild albuminuria was also observed and was more pronounced in male mice, suggesting possible sex-specific susceptibility.
In human glomerular microvascular endothelial cells (HGMECs), CPT2 knockdown altered mitochondrial morphology, reduced staining of the endothelial marker CD31 (PECAM-1), compromised cell-cell junction integrity, and induced inflammatory and endothelial activation genes (IL6, CCL2, VCAM1, and ICAM1) as well as ANGPT2, a marker associated with endothelial destabilization. Acetate supplementation partially attenuated CPT2 knockdown-induced inflammatory transcriptional responses.
Together, this work identifies endothelial FAO as a metabolic regulator of endothelial identity and renal fibrotic remodeling. By linking FAO-derived acetyl-CoA to EndoMT-like endothelial plasticity, the study provides a broader experimental framework for understanding metabolic mechanisms of chronic kidney injury. The FAO-acetyl-CoA axis, including strategies that restore acetyl-CoA availability, merits further investigation as a potential avenue for chronic kidney disease intervention.
DOI
10.1093/lifemeta/loag017