SUL-138 mitigates accelerated endothelial aging and protects the kidney

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Nephrology

Background:

• Vascular aging involves increased reactive oxygen species and DNA damage in endothelial cells, leading to impaired vasodilation and potential kidney dysfunction.
• Mitochondrial dysfunction is a key contributor to endothelial cell aging and DNA damage response, exacerbating vascular aging.
• Accelerated endothelial aging negatively impacts peripheral organs, exemplified by kidney tubular injury and dysfunction.

Purpose of the Study:

• To investigate the effects of SUL-138, a mitochondrial protective compound, on DNA damage-induced endothelial aging and kidney dysfunction in mice.
• To determine if SUL-138 can restore endothelial cell function and mitigate associated kidney pathologies.
• To elucidate the mechanisms by which SUL-138 impacts vascular function and kidney health.

Main Methods:

• Induction of endothelial-specific accelerated aging in mice via knockout of the DNA repair endonuclease Ercc1 (EC-KO mice).
• Chronic treatment of EC-KO mice with SUL-138 (30 mg/kg/day).
• Assessment of endothelial function, DNA damage markers, mitochondrial function, and kidney histology and function.

Main Results:

• SUL-138 treatment restored impaired endothelium-dependent vasodilation in EC-KO mice.
• The compound increased endothelium-derived hyperpolarization (EDH), the mechanism underlying improved vasodilation.
• SUL-138 normalized kidney tubular injury, sodium wasting, and inflammatory markers in EC-KO mice.

Conclusions:

• Accelerated endothelial aging, driven by DNA damage response, impairs vascular function and causes kidney tubular injury.
• SUL-138 effectively rescues endothelial aging, improves vasodilation via EDH, and protects against kidney damage.
• Preserving mitochondrial function represents a promising therapeutic strategy for aging-related vascular and kidney dysfunction.