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Endothelial DNA Damage Orchestrates Cardio-Kidney-Metabolic Dysfunction Through Endothelin-1 Signaling.

Wataru Ito1, Ran Nakamichi1, Akihito Hishikawa1

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Summary

Endothelial DNA damage drives cardiovascular, metabolic, and kidney dysfunction via the endothelin-1 pathway. Blocking endothelin type A receptor (ETAR) offers a therapeutic strategy for age-related diseases.

Keywords:
atrasentanblood pressurecardiovascular diseasesdyslipidemiaendothelial cells

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Area of Science:

  • Cardiovascular Biology
  • Metabolic Disease Research
  • Renal Aging Studies

Background:

  • Aging exacerbates cardiovascular diseases, metabolic dysfunction, and kidney disease.
  • Endothelial cells (ECs) are vulnerable to aging stressors like DNA damage.
  • The molecular mechanisms linking EC DNA damage to cardiovascular-kidney-metabolic (CKM) dysfunction are unclear.

Purpose of the Study:

  • To investigate if EC DNA damage drives CKM dysfunction.
  • To elucidate the molecular pathways involved in EC DNA damage-induced CKM dysfunction.
  • To evaluate ETAR blockade as a therapeutic strategy for CKM dysfunction.

Main Methods:

  • Generated mice with EC-specific DNA double-strand breaks using endonuclease I-PpoI.
  • Subjected mice to a high-fat diet (HFD) to induce CKM dysfunction.
  • Analyzed EC DNA damage markers (γH2AX) and correlated them with clinical parameters in human kidney biopsies.

Main Results:

  • HFD-fed mice with EC DNA damage developed hypertension, dyslipidemia, hepatic steatosis, and visceral fat accumulation.
  • EC DNA damage triggered endothelin-1 (ET-1) secretion, leading to hepatic hypoxia, ETAR activation, and lipid metabolic reprogramming via ACSS2.
  • Atrasentan (selective ETAR antagonist) normalized CKM parameters and attenuated renal aging.
  • Human EC DNA damage correlated with impaired kidney function, dyslipidemia, and hepatic steatosis.

Conclusions:

  • Endothelial DNA damage is a key driver of CKM dysfunction through the ET-1-ETAR-ACSS2 pathway.
  • ETAR blockade is a promising mechanism-based therapeutic strategy for age-related CKM diseases.