Sirtuin-1 ameliorates cadmium-induced endoplasmic reticulum stress and pyroptosis through XBP-1s deacetylation in human renal tubular epithelial cells.

Abstract

Cadmium (Cd), an occupational and environmental pollutant, induces nephrotoxicity by primarily damaging renal proximal tubular cells. In this study, we hypothesized that pyroptosis, a caspase-1-dependent inflammatory programmed cell death mechanism, mediates Cd-induced nephrotoxicity. Human proximal tubular epithelial HK-2 cells were treated with 0-10µM CdCl2 for 48h. We found that Cd dose-dependently caused cytotoxicity, which correlated with activation of the NLRP3 inflammasome, increases in the expression and secretion of pro-inflammatory cytokines and upregulation of pyroptosis-related genes in HK-2 cells or/and in kidneys of Cd-treated mice. These effects were significantly abrogated by inhibiting caspase-1 activity with inhibitor YVAD or silencing NLRP3 with siRNA in vitro, suggesting that Cd induces caspase-1- and NLRP3-inflammasome-dependent pyroptosis. Moreover, Cd treatment also activated three branches (ATF6, PERK and IRE-1α) of endoplasmic reticulum stress. Selective inhibition of the IRE-1α/XBP-1s branch by a pharmacological inhibitor STF-083010 or by genetic silencing of XBP-1 significantly attenuated Cd-induced NLRP3 inflammasome activation and pyroptosis. Mechanistically, Cd suppressed deacetylase Sirtuin-1 (SIRT-1) protein expression and activity leading to decrease in physical binding with XBP-1s protein, and thus the accumulation of acetylated XBP-1s levels. Activation of SIRT1 using a pharmacological agonist resveratrol or genetic SIRT1 overexpression significantly abolished Cd-induced activation of the IRE-1α/XBP-1s pathway and the NRLP3 inflammasome as well as pyroptosis, which were counteracted by co-overexpression of both SIRT1 and XBP-1s. Collectively, our findings indicate that SIRT1 activity protects against Cd-induced pyroptosis through deacetylating XBP-1s, and thus inhibiting the IRE-1α/XBP-1s pathway in HK-2 cells. These results provide a novel mechanism for Cd-induced nephrotoxicity.