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Renal Protective Effect of Hydrogen Sulfide in Cisplatin-Induced Nephrotoxicity

2018; Mary Ann Liebert, Inc.; Volume: 29; Issue: 5 Linguagem: Inglês

10.1089/ars.2017.7157

1557-7716

Xu Cao, Siping Xiong, Ye‐Bo Zhou, Zhiyuan Wu, Lei Ding, Yike Zhu, Mark E. Wood, Matthew Whiteman, Philip K. Moore, Jin‐Song Bian,

Lanthanide and Transition Metal Complexes

Cisplatin is a major therapeutic drug for solid tumors, but can cause severe nephrotoxicity. However, the role and therapeutic potential of hydrogen sulfide (H2S), an endogenous gasotransmitter, in cisplatin-induced nephrotoxicity remain to be defined.Cisplatin led to the impairment of H2S 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. H2S donors NaHS and GYY4137, but not AP39, mitigated cisplatin-induced RPT cell death and nephrotoxicity. The mechanisms underlying the protective effect of H2S 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 H2S in cisplatin-induced nephrotoxicity. Our results indicate that H2S may be a novel and promising therapeutic target to prevent cisplatin-induced nephrotoxicity. Antioxid. Redox Signal. 29, 455-470.