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

Archives of Toxicology
Xin ChouQing Wu

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 (S...Continue Reading

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Citations

Feb 6, 2021·Archives of Toxicology·Hu LiXingxiang Chen
Nov 1, 2020·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Jian-Ri LiChun-Jung Chen
Feb 23, 2021·American Journal of Physiology. Renal Physiology·Fei DengYashpal S Kanwar
May 25, 2021·Archives of Toxicology·Alexey A TinkovMichael Aschner
Jul 11, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Ghedeir M AlshammariMohammed Abdo Yahya
Aug 8, 2021·International Journal of Molecular Sciences·Md Jamal UddinHunjoo Ha
Aug 14, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Fuquan WangHaifa Xia

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Methods Mentioned

BETA
Transfection
PCR
protein assay
acetylation
ELISA
pulldowns
nuclear translocation

Software Mentioned

Image J
SPSS

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