Hydrogen Sulfide Attenuates Cisplatin-Induced Acute Kidney Injury via Dual Inhibition of Apoptosis and Pyroptosis

TL;DR

Hydrogen sulfide reduces kidney damage from cisplatin by blocking two types of cell death, offering a potential new treatment.

Contribution

This study reveals hydrogen sulfide's dual inhibition of apoptosis and pyroptosis in cisplatin-induced kidney injury.

Findings

Apoptotic signaling peaked at 24 hours, while pyroptosis was activated later at 72 hours.

GYY4137 reduced serum creatinine and BUN levels by 22.64% and 22.5%, respectively.

Hydrogen sulfide suppressed both early apoptosis and delayed pyroptosis without reversing CBS downregulation.

Abstract

Purpose: Cisplatin chemotherapy is complicated by acute kidney injury (cis-AKI), driven by regulated cell death pathways, including apoptosis and pyroptosis. However, the temporal relationship between apoptosis and pyroptosis in cis-AKI remains unclear. This study investigated the roles of these pathways and evaluated the renoprotective effect of the hydrogen sulfide (H2S) donor GYY4137. Method: Cis-AKI was modeled in mice and HK2 cells, divided into control, cisplatin, and cisplatin + GYY groups. Kidney function parameters, histopathology, and cell death were evaluated. Markers of apoptosis and pyroptosis, along with the H2S-producing enzyme, were analyzed. Results: Renal impairment progressed from BUN elevation to increased Scr, coupled with aggravated renal tissue damage. Apoptotic signaling peaked at 24 h, evidenced by a raised Bax/Bcl-2 ratio and caspase-3 cleavage. Pyroptosis pathways, via both NLRP3/caspase-1/GSDMD and caspase-3/GSDME axes, were activated later at 72 h, with concurrent rises in IL-1β and IL-18. GYY4137 treatment significantly ameliorated renal dysfunction, reducing serum creatinine and BUN levels by 22.64% and 22.5%, respectively. It suppressed both the early apoptotic and delayed pyroptosis cascades without reversing CBS downregulation. Conclusions: GYY4137 mitigated both apoptosis and pyroptosis, offering a promising multi-targeted therapy for cis-AKI.

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