Cadmium induces renal inflammation by activating the NLRP3 inflammasome through ROS/MAPK/NF-κB pathway in vitro and in vivo.

Abstract

Cadmium (Cd) has been reported to induce kidney damage by triggering oxidative stress and inflammation. The NLR family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated a role in the pathogenesis of inflammation. However, the connection between Cd and NLRP3 inflammasome in the development of renal inflammation remains unknown. In this study, in vitro experiments based on the telomerase-immortalized human renal proximal-tubule epithelial cell line (RPTEC/TERT1) were carried out. Results revealed that CdCl2 (2-8 μM) increased ROS production and activated NLRP3, thereby enhancing secretion of IL-1β and IL-18 (P < 0.05). Knock-down of NLRP3 rescued the RPTEC/TERT1 cells from Cd-induced inflammatory damage. Cd activated the MAPK/NF-κB signaling pathway in RPTEC/TERT1 cells (P < 0.05). In addition, treatment with N-acetylcysteine (NAC) improved inflammation and blocked the upregulation of the MAPK/NF-κB signaling pathway. Pre-treatment with MAPK and NF-κB inhibitors also suppressed NLRP3 inflammasome activation (P < 0.05). Moreover, CdCl2 (25-00 mg/L) stimulated the MAPK/NF-κB signaling pathway, activated the NLRP3 inflammasome, and increased inflammatory response (P < 0.05) leading to renal injury in rats. Exposure to cadmium elevated serum levels of NLRP3 and IL-1β in populations (P < 0.05). Further analysis found that serum NLRP3 and IL-1β levels were positively correlated with urine cadmium (UCd) and urine N-acetyl-β-D-glucosaminidase (UNAG). Overall, Cd induced renal inflammation through the ROS/MAPK/NF-κB signaling pathway by activating the NLRP3 inflammasome. Our research thus provides new insights into the molecular mechanism that NLRP3 contributes to Cd-induced kidney damage.

• Authors: Ziyin Li, Huiqin Chi, Wei Zhu, Guangyu Yang, Jia Song, Lijun Mo, Yitian Zhang, Yudi Deng, Feifei Xu, Jiani Yang, Zhini He, Xingfen Yang
• Journal: Archives of toxicology (Arch Toxicol) Vol. 95 Issue 11 Pg. 3497-3513 (Nov 2021) ISSN: 1432-0738 [Electronic] Germany
• PMID: 34510229 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Inflammasomes
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species
• Cadmium
• Mitogen-Activated Protein Kinase Kinases

Topics

• Acute Kidney Injury (chemically induced)
• Animals
• Cadmium (toxicity, urine)
• Cell Line, Transformed
• Female
• Humans
• Inflammasomes
• Inflammation (etiology)
• Kidney (drug effects, pathology)
• Kidney Tubules, Proximal
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Signal Transduction