SIRT1 alleviates Cd nephrotoxicity through NF-κB/p65 deacetylation-mediated pyroptosis in rat renal tubular epithelial cells.

Abstract

Cadmium (Cd) is a widely distributed environmental pollutant, primarily causing nephrotoxicity through renal proximal tubular cell impairment. Pyroptosis is an inflammation-related nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3)-dependent pathway for programmed cell death. We previously reported that inappropriate inflammation caused by Cd is a major contributor to kidney injury. Therefore, research on Cd-induced inflammatory response and pyroptosis may clarify the mechanisms underlying Cd-induced nephrotoxicity. In this study, we observed that Cd-induced nephrotoxicity is associated with NLRP3 inflammasome activation, leading to an increase in proinflammatory cytokine expression and secretion, as well as pyroptosis-related gene upregulation, both in primary rat proximal tubular (rPT) cells and kidney tissue from Cd-treated rats. In vitro, these effects were significantly abrogated through siRNA-based Nlrp3 silencing; thus, Cd may trigger pyroptosis through an NLRP3 inflammasome-dependent pathway. Moreover, Cd exposure considerably elevated reactive oxygen species (ROS) content. N-acetyl-l-cysteine, an ROS scavenger, mitigated Cd-induced NLRP3 inflammasome activation and subsequent pyroptosis. Mechanistically, Cd hindered the expression and deacetylase activity of SIRT1, eventually leading to a decline in SIRT1-p65 interactions, followed by an elevation in acetylated p65 levels. The administration of resveratrol (a SIRT1 agonist) or overexpression of Sirt1 counteracted Cd-induced RELA/p65/NLRP3 pathway activation considerably, leading to pyroptosis. This is the first study to reveal significant contributions of SIRT1-triggered p65 deacetylation to pyroptosis and its protective effects against Cd-induced chronic kidney injury. Our results may aid in developing potential therapeutic strategies for preventing Cd-induced pyroptosis through SIRT1-mediated p65 deacetylation.

• Authors: Wenxuan Dong, Kanglei Zhang, Xueru Wang, Jiahui Li, Hui Zou, Yan Yuan, Jianhong Gu, Jiaqiao Zhu, Gang Liu, Zongping Liu, Ruilong Song
• Journal: The Science of the total environment (Sci Total Environ) Vol. 929 Pg. 172392 (Jun 15 2024) ISSN: 1879-1026 [Electronic] Netherlands
• PMID: 38608885 (Publication Type: Journal Article)
• Copyright: Copyright © 2024 Elsevier B.V. All rights reserved.

Chemical References

• Sirtuin 1
• Cadmium
• NF-kappa B
• Sirt1 protein, rat
• NLR Family, Pyrin Domain-Containing 3 Protein
• Transcription Factor RelA
• Inflammasomes
• Nlrp3 protein, rat

Topics

• Animals
• Sirtuin 1 (metabolism)
• Pyroptosis (drug effects)
• Cadmium (toxicity)
• Rats
• Epithelial Cells (drug effects)
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Kidney Tubules
• Transcription Factor RelA (metabolism)
• Acetylation
• Inflammasomes (metabolism)
• Kidney Tubules, Proximal