Lithium intoxication induced pyroptosis via ROS/NF‐κB/NLRP3 inflammasome regulatory networks in kidney of mice

• Published in: Environmental toxicology Vol. 37; no. 4; pp. 825 - 835
• Main Authors: Jing, Hongyuan, Wang, Fuhan, Gao, Xue‐jiao
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.04.2022; Wiley Subscription Services, Inc
• Subjects: Animal models; Animals; antioxidant activity; antioxidant enzymes; Antioxidants; Apoptosis; Carbonates; Catalase; Cells; Contaminants; Damage accumulation; DNA nucleotidylexotransferase; ecotoxicology; Glutathione; Glutathione peroxidase; Histopathology; humans; immunohistochemistry; Inflammasomes; Inflammasomes - metabolism; Inflammation; Intoxication; kidney; Kidney - pathology; Kidneys; Lithium; Lithium - toxicity; Lithium carbonate; Mental disorders; Mice; Necrosis; Neoplasms; Nephrotic syndrome; NF-kappa B - metabolism; NF‐κB; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Nucleotides; Oligomerization; Peroxidase; poisoning; Pyroptosis; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors; Salts; Signal transduction; Superoxide dismutase; Western blotting; NF-κB; kidney; lithium; pyroptosis; NLRP3 inflammasome
• ISSN: 1520-4081; 1522-7278; 1522-7278
• DOI: 10.1002/tox.23446

Humans and animals may be exposed to increasing contaminant lithium (Li) concentrations in the environment with the use and disposal of Li‐containing products. Meanwhile, Li plays a key role in the treatment of human mental disorders, while the excessive accumulation of Li salts in the body can cause renal damage and nephrotic syndrome. In this study, the mechanism of renal inflammatory reaction induced by Li excessive intake was studied by establishing mice models in vitro and in vivo. The results of histopathology staining and TdT‐mediated dUTP nick‐end labeling assay showed that high Li condition (Lithium carbonate, 20 mg/kg/twice a day, i.e., for 30 consecutive days) caused inflammatory damage and apoptosis in kidney tissue cells. Western blot, qPCR, and immunohistochemical analysis were used to further study. In the vivo experiments, we found that Li reduced antioxidant enzyme capacity (glutathione peroxidase, total superoxide dismutase, total antioxidant capacity, and catalase) and induced the production of reactive oxygen species (ROS). Moreover, excessive Li activated nuclear factor kappa‐B (NF‐κB) signaling pathway and nucleotide‐binding oligomerization domain‐like receptors domains–containing protein 3 (NLRP3) inflammasome, resulting in activation of inflammatory factors tumor necrosis factor‐α and IL‐1β in the kidney of mice. In the vitro study, ROS as an upstream signal phosphorylated IκBα and NF‐κB, up‐regulated the NLRP3 inflammasome, increased caspase3, 6, 7, and 9 to exaggerate inflammation response, finally inducing pyroptosis in renal cells.