Metformin Alleviates High Glucose‐Induced Pyroptosis and Inflammatory Responses in
HK
‐2 Cells via
SIRT1
‐Associated Regulation of the
Shuyu Shi, Bing Wang, Yang Zhou, Qi Li, Yusheng Hou, Xinyi Zhang, Qiuyue Wang ABSTRACT
Background
Diabetic kidney disease (DKD) is a major cause of renal failure and end‐stage renal disease. Pyroptosis, a Gasdermin‐dependent inflammatory form of programmed cell death, has been implicated in DKD progression. Metformin has shown renoprotective effects in DKD; however, the underlying mechanisms remain unclear.
Objective
To investigate whether metformin attenuates high glucose‐induced pyroptosis and inflammatory responses in HK‐2 cells through SIRT1‐mediated regulation of the TXNIP/NLRP3 pathway.
Methods
Bioinformatics analyses were performed to identify DKD‐related pyroptosis‐associated genes and enriched pathways. Serum TXNIP and IL‐1β levels were measured in patients with type 2 diabetes mellitus stratified by urinary albumin‐to‐creatinine ratio (UACR). HK‐2 cells were exposed to high glucose (30 mM) to establish an in vitro injury model. Oxidative stress, pyroptosis‐related signalling and inflammatory cytokines were evaluated using molecular and immunological assays. SIRT1 modulation and TXNIP silencing were used to investigate pathway regulation. Chromatin immunoprecipitation assays were performed to assess SIRT1 occupancy and histone acetylation status within the TXNIP promoter region.
Results
Pyroptosis‐related genes were mainly enriched in inflammatory and NLRP3 inflammasome‐associated pathways. Serum TXNIP and IL‐1β levels were elevated in DKD patients and positively correlated with UACR. In HK‐2 cells, high glucose reduced SIRT1 expression and activated the TXNIP/NLRP3 inflammasome pathway, accompanied by increased GSDMD cleavage and inflammatory cytokine expression. Metformin partially reversed these changes. Altered SIRT1 activity was also associated with changes in H3K56 acetylation enrichment within the TXNIP promoter region.
Conclusion
Metformin may alleviate high glucose‐induced pyroptosis and inflammatory responses in HK‐2 cells, potentially through modulation of SIRT1‐associated TXNIP/NLRP3 signalling and TXNIP‐related chromatin acetylation status.