Diallyl Trisulfide Attenuates Ischemia-Reperfusion-Induced ER Stress and Kidney Dysfunction in Aged Female Mice

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in the aging population. Gender studies show that aging is associated with loss of protection from AKI in the female population. While ER stress contributes to IRI-induced AKI in the young, ER regulation during IR in the aged kidney is unclear. Because current evidence suggests hydrogen sulfide (H₂S) modulates ER stress, we investigated whether exogenous supplementation of diallyl trisulfide (DATS), an H₂S donor, mitigates AKI in aged female kidneys. Wild-type (WT, C57BL/6J) mice aged 75-78 weeks were treated with or without DATS before and after renal IRI. IRI increased ER stress proteins, inflammation, and fibrosis markers in the IRI kidney compared to the control. DATS mitigated ER stress, and reduced inflammation and fibrosis markers in the IRI kidney. Further, IRI kidneys demonstrated reduced blood flow, vascularity, angiogenesis, increased resistive index (RI), and reduced function. DATS treatment upregulated PI3K, AKT, p-mTOR, and pMAPK signaling to stimulate angiogenesis, which improved vascular density, blood flow, and renal function. Together, our results suggest that DATS rescues the aged female kidney IRI by modulating ER stress and upregulation of angiogenesis.