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Magnesium hydride protects against acetaminophen-induced acute kidney injury by inhibiting TXNIP/NLRP3/nf-κb pathway.

ABSTRACT: Acetaminophen (APAP)-induced acute kidney injury (APAP-AKI) has turned into one of reasons for clinic obtained renal insufficiency. Magnesium hydride (MgH₂), as a solid-state hydrogen source, might be potentially applied in clinical practice. The current study aimed to investigate the protective effect of MgH₂ against APAP-AKI. The results showed that MgH₂ improved renal function and histological injury in mice of APAP-AKI. MgH₂ also had protective effects on APAP-induced cytotoxicity in HK-2 cells. In addition, the increased level of reactive oxygen species (ROS) and expressions of inflammatory cytokines (TNF-α and IL-1β) and pro-apoptotic factors (Bad, Bax, Caspase3, and CytC) induced by APAP were downregulated with MgH₂ treatment. Furthermore, the expressions of molecules related to TXNIP/NLRP3/NF-κB pathway (TXNIP, NLRP3, NF-κB p65 and p-NF-κB p65) in renal tissues and HK-2 cells were enhanced by APAP overdose, which were reduced by MgH₂ administration. Collectively, this study indicated that MgH₂ protects against APAP-AKI by alleviating oxidative stress, inflammation and apoptosis via inhibition of TXNIP/NLRP3/NF-κB signaling pathway.

SUBMITTER: Si Y

PROVIDER: S-EPMC10946266 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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Magnesium hydride protects against acetaminophen-induced acute kidney injury by inhibiting TXNIP/NLRP3/nf-κb pathway.

Si Yachen Y Liu Lulu L Zhang Yinyin Y Li Hongxia H Zhao Tingting T Liu Su S Sun Xuejun X Cheng Jin J Lu Hongtao H

Renal failure 20240317 1

Acetaminophen (APAP)-induced acute kidney injury (APAP-AKI) has turned into one of reasons for clinic obtained renal insufficiency. Magnesium hydride (MgH2), as a solid-state hydrogen source, might be potentially applied in clinical practice. The current study aimed to investigate the protective effect of MgH2 against APAP-AKI. The results showed that MgH2 improved renal function and histological injury in mice of APAP-AKI. MgH2 also had protective eff ...[more]

PMID: 38494199

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Project description:Acetaminophen (APAP) overdose is the primary cause of drug‑induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role in the pathogenesis of various forms of acute liver injury. However, the cellular source for NLRP3 induction and its involvement during APAP‑induced hepatotoxicity have not been thoroughly investigated. In the present study, hematoxylin and eosin staining was performed to assess histopathological changes of liver tissue. Immunohistochemistry staining(NLRP3, Caspase‑1, IL‑1β, GSDMD and Caspase‑3), western blotting (NLRP3, Caspase‑1, IL‑1β, GSDMD and Caspase‑3) and RT‑qPCR (NLRP3, Caspase‑1 and IL‑1β) were performed to assess the expression of NLRP3/GSDMD signaling pathway. TUNEL staining was performed to assess apoptosis of liver tissue. The serum expression levels of inflammatory factors (IL‑6, IL‑18, IL‑1β and TNF‑α) were assessed using ELISA and inflammation of liver tissue was assessed using immunohistochemistry (Ly6G and CD68) and RT‑qPCR (TNF‑α, Il‑6, Mcp‑1, Cxcl‑1, Cxcl‑2). A Cell Counting Kit‑8 was performed to assess cell viability and apoptosis. Protein and gene expression were analyzed by western blotting (PCNA, CCND1) and RT‑qPCR (CyclinA2, CyclinD1 and CyclinE1). Through investigation of an APAP‑induced acute liver injury model (AILI), the present study demonstrated that APAP overdose induced activation of NLRP3 and cleavage of gasdermin D (GSDMD) in hepatocytes, both in vivo and in vitro. Additionally, mice with hepatocyte‑specific knockout of Nlrp3 exhibited reduced liver injury and lower mortality following APAP intervention, accompanied by decreased infiltration of inflammatory cells and attenuated inflammatory response. Furthermore, pharmacological blockade of NLRP3/GSDMD signaling using MCC950 or disulfiram significantly ameliorated liver injury and reduced hepatocyte death. Notably, hepatocyte Nlrp3 deficiency promoted liver recovery by enhancing hepatocyte proliferation. Collectively, the present study demonstrated that inhibition of the NLRP3 inflammasome protects against APAP‑induced acute liver injury by reducing hepatocyte pyroptosis and suggests that targeting NLRP3 may hold therapeutic potential for treating AILI.

Dataset Information

Magnesium hydride protects against acetaminophen-induced acute kidney injury by inhibiting TXNIP/NLRP3/nf-κb pathway.

Publications

Magnesium hydride protects against acetaminophen-induced acute kidney injury by inhibiting TXNIP/NLRP3/nf-κb pathway.

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