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Endothelial DNA damage orchestrates cardio-kidney-metabolic dysfunction through ET-1/ETAR signaling.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE318719 | GEO | 2026/02/11

REPOSITORIES: GEO

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Endothelial DNA damage orchestrates cardio-kidney-metabolic dysfunction through ET-1/ETAR signaling.

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