Hydrogen sulfide attenuates uranium-induced kidney cells pyroptosis via upregulation of PI3K/AKT/mTOR signaling

We have identified that hydrogen sulfide (H2S), a gaseous mediator, plays a crucial role in antioxidative, anti-inflammatory, and cytoprotective effects on uranium (U)-triggered rat nephrotoxicity. Pyroptosis is a special mode of inflammation and programmed cell death involved in the activation of inflammasome and Caspase-1 and the release of inflammatory cytokines. This study aims to confirm whether H2S can alleviate U-induced rat NRK-52(E) cell pyroptosis and to investigate the H2S underlying regulatory mechanism. Our results indicate that pretreatment with NaHS (an H2S donor) significantly inhibited U-increased reactive oxygen species level, NLRP3, apoptosis-related speck-like protein consisting of a caspase recruitment domain (ASC), and cleaved Caspase-1 proteins expression, gasdermin D messenger RNA (GSDMD mRNA) expression, interleukin (IL)-1 beta and IL-18 contents, lactate dehydrogenase leakage, and numbers of double-positive dying kidney cells. NaHS application evidently augmented phosphorylated PI3K, AKT, and mTOR expression as well as ratios of their respective phosphorylation to the corresponding total proteins which were downregulated by U treatment. But, LY294002 (a PI3K inhibitor) administration effectively abrogated the consequences of NaHS on the levels of p-PI3K, cleaved Caspase-1, ASC and NLRP3 proteins, GSDMD mRNA expression, and (IL)-1 beta and IL-18 contents. Simultaneously, LY294002 significantly reversed the effects of NaHS on U-induced pyroptosis rate and cytotoxicity. Taken together, these results indicate that H2S ameliorated U-triggered NRK-52(E) cells pyroptosis via upregulation of PI3K/AKT/mTOR pathway, suggesting a novel role for H2S in the management of nephrotoxicity caused by U exposure.