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.
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Abbreviations
- ATF6:
-
Activating transcription factor 6
- Cd:
-
Cadmium
- ER:
-
Endoplasmic reticulum
- IRE-1α:
-
Inositol-requiring enzyme 1α
- NLRP3:
-
Nucleotide-binding oligomerization segment-like receptor family 3 inflammasome
- PERK:
-
Protein kinase RNA-like endoplasmic reticulum kinase
- XBP-1s:
-
Splice X-box binding protein-1
- SIRT1:
-
Sirtuin-1
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Acknowledgements
This study was supported by Grant (no. 21277033) from the national Natural Science Foundation of China; Grant (no. 14DZ2260200, the Project of Shanghai Key Laboratory of Kidney and Blood Purification) from the Scienceand Technology Commission of Shanghai Municipality; Program of China-Sri Lanka Joint Research and Demonstration Center for Water Technology and China-Sri Lanka Joint Center for Education and Research by Chinese Academy of Sciences, China and Grant (no. 15GWZK0202) from the Fourth Round of Three-year Public Health Action Plan of Shanghai. The authors thank Dr. Wusheng Xiao for his critical language editing of this manuscript.
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Chou, X., Ding, F., Zhang, X. et al. Sirtuin-1 ameliorates cadmium-induced endoplasmic reticulum stress and pyroptosis through XBP-1s deacetylation in human renal tubular epithelial cells. Arch Toxicol 93, 965–986 (2019). https://doi.org/10.1007/s00204-019-02415-8
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DOI: https://doi.org/10.1007/s00204-019-02415-8