Endothelial DNA damage orchestrates cardio-kidney-metabolic dysfunction through ET-1/ETAR signaling.
DNA damage, a hallmark of aging, is a major trigger of inflammation and age-related pathologies. Here, we show that vascular endothelial cells (ECs) exhibit a distinct response to DNA damage, characterized by dysregulation of endocrine signaling via ET-1. EC-specific DNA double strand breaks under high-fat diet conditions led to a rapid elevation of blood pressure, dyslipidemia, hepatic steatosis, visceral fat accumulation and kidney aging. Elevated EC-derived endothelin-1 (ET-1) triggered liver hypoxia and ET-A receptor (ETAR) activation, promoting lipid metabolic reprogramming via increased acetyl-CoA synthetase 2 (ACSS2), and ETAR inhibition mitigated these phenotypes. In humans, kidney EC DNA damage correlated with reduced eGFR and HDL-C, and increased hepatic steatosis indices. Collectively, EC DNA damage is a possible driver of cardio-kidney-metabolic dysfunction via ET-1-ACSS2 signaling, which is targetable by ETAR blockade. These findings highlight the organ-specific impact of endothelial cell DNA damage in driving cardio-kidney-metabolic dysfunction. Overall design: RNA-sequencing was performed on endothelial cells isolated from kidneys of endothelial-specific I-PpoI-expressing mice and control littermates (n=3 per group) after 4 weeks of high-fat diet feeding.