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

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

Journal of biochemical and molecular toxicology (2022-09-13)
Qiaoni Hu, Rui Zhang, Jifang Zheng, Menghui Song, Chaohao Gu, Wanting Li
ABSTRACT

We have identified that hydrogen sulfide (H2 S), 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 H2 S can alleviate U-induced rat NRK-52E cell pyroptosis and to investigate the H2 S underlying regulatory mechanism. Our results indicate that pretreatment with NaHS (an H2 S 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)-1β 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)-1β 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 H2 S ameliorated U-triggered NRK-52E cells pyroptosis via upregulation of PI3K/AKT/mTOR pathway, suggesting a novel role for H2 S in the management of nephrotoxicity caused by U exposure.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-AKT1 (Ab-450) antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Anti-mTOR antibody produced in rabbit, 1.0-1.5 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anti-Caspase 1 Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-PI3 Kinase Antibody, p85, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Anti-ASC antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Anti-phospho-PI3-kinase p85-α (pTyr607) antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Anti-phospho-mTOR (pThr2446) antibody produced in rabbit, affinity isolated antibody