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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 0-10 µM CdCl2 for 48 h. 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.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Chou X,Ding F,Zhang X,Ding X,Gao H,Wu Q

doi

10.1007/s00204-019-02415-8

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

965-986

issue

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-019-02415-8

journal_volume

pub_type

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