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During the congress, E-Posters will be accessible to all participants on the congress website 24/7, as well as in the E-poster stations in the congress center.
Preparing your E-Poster
Please review the E-Poster format requirements carefully when preparing your E-Poster. Should your E-Poster not meet the mentioned requirements, it may not be displayed as described above.
E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
Please follow the instructions below to input your abstract title.
Abstract titles should be brief and reflect the content of the abstract.
Cardiovascular-kidney-metabolic (CKM) dysfunction increases with aging. Vascular endothelial cells (ECs) are vulnerable to aging stressors like DNA damage, suggesting a central role for endothelial dysfunction in CKM pathogenesis. Our previous work demonstrated that DNA damage in renal cells, such as podocytes and proximal tubular cells, induces immunosenescence and age-related metabolic changes (Cell rep 2023, Nat Commun 2025). However, the specific impact of the endothelial DNA damage response in driving the pathology of age-related diseases remains unclear. Therefore, this study aimed to investigate how EC DNA damage orchestrates CKM dysfunction and to elucidate the underlying molecular pathways.
We generated mice with EC-specific DNA double-strand breaks using the I-PpoI endonuclease system (I-PpoI mice). To unmask latent pathologies, mice were challenged with a high-fat diet (HFD) starting at 8 weeks of age. This approach allowed us to investigate the impact of EC-specific DNA damage on cardiovascular, metabolic, and renal systems. Furthermore, we analyzed the correlation between EC DNA damage marker, γH2AX, and clinical parameters in human kidney biopsy samples.
Under HFD, I-PpoI mice rapidly developed hypertension, dyslipidemia (reduced HDL-C), hepatic steatosis, and visceral fat accumulation, resulting in a phenotype similar to metabolic syndrome. Concurrently, these mice exhibited accelerated renal aging, marked by increased senescence markers. Elevated urinary Endothelin-1 (ET-1) was detected early in I-PpoI mice, and DNA damage induced ET-1 secretion in cultured human endothelial cells. RNA-sequencing analysis of isolated ECs further revealed the upregulation of ACSS2, a master regulator of lipogenesis and a factor implicated in promoting senescence. Mechanistically, Elevated ET-1 induced hepatic hypoxia and direct ETAR activation, driving metabolic reprogramming via ACSS2 upregulation and subsequent lipogenesis. Pharmacological ETAR blockade with Atrasentan reversed these phenotypes—normalizing blood pressure, resolving hepatic steatosis, restoring HDL-C, reducing visceral fat, and attenuating renal senescence—by interrupting the ET-1-ETAR-ACSS2 cascade. In human kidneys, EC DNA damage correlated negatively with eGFR and HDL-C, and positively with the Hepatic Steatosis Index and renal cortical ETAR expression, consistent with the results from the mouse model.
This study identifies endothelial DNA damage as a pivotal orchestrator of CKM dysfunction. The EC response to DNA damage drives pathology primarily through endocrine dysregulation via the ET-1-ETAR-ACSS2 signaling cascade, rather than immune activation. Targeting this pathway with ETAR blockade offers a mechanism-based, comprehensive therapeutic strategy for age-related CKM syndrome.
