Renal Protective Effect of Hydrogen Sulfide in Cisplatin-Induced Nephrotoxicity.

AIMS

Cisplatin is a major therapeutic drug for solid tumors, but can cause severe nephrotoxicity. However, the role and therapeutic potential of hydrogen sulfide (HS), an endogenous gasotransmitter, in cisplatin-induced nephrotoxicity remain to be defined.

RESULTS

Cisplatin led to the impairment of HS production in vitro and in vivo by downregulating the expression level of cystathionine γ-lyase (CSE), which may contribute to the subsequent renal proximal tubule (RPT) cell death and thereby renal toxicity. HS donors NaHS and GYY4137, but not AP39, mitigated cisplatin-induced RPT cell death and nephrotoxicity. The mechanisms underlying the protective effect of HS donors included the suppression of intracellular reactive oxygen species generation and downstream mitogen-activated protein kinases by inhibiting NADPH oxidase activity, which may be possibly through persulfidating the subunit p47phox. Importantly, GYY4137 not only ameliorated cisplatin-caused renal injury but also added on more anticancer effect to cisplatin in cancer cell lines. Innovation and Conclusion: Our study provides a comprehensive understanding of the role and therapeutic potential of HS in cisplatin-induced nephrotoxicity. Our results indicate that HS may be a novel and promising therapeutic target to prevent cisplatin-induced nephrotoxicity. Antioxid. Redox Signal. 29, 455-470.