TIMP2 protects against sepsis-associated acute kidney injury by cAMP/NLRP3 axis-mediated pyroptosis

• DOI: 10.1152/ajpcell.00577.2023
• Publication Date: 2024-03-18T08:21:25Z
• Authors: Dongxue Xu; Jun Jiang; Ye Liu; Jingjing Pang; Jinmeng Suo; Yiming Li; Zhiyong Peng
• Keywords: Pyroptosis

The tissue inhibitor of metalloproteinases 2 (TIMP2) has emerged as a promising biomarker for predicting the risk sepsis-associated acute kidney injury (SA-AKI). However, its exact role in SA-AKI and underlying mechanism remains unclear. In this study, we investigated impact tubule-specific Timp2 knockout mice on inflammation. Our findings demonstrated that Timp2-knockout exhibited more severe than wild-type mice, along with elevated levels pyroptosis markers NOD-like receptor protein 3 (NLRP3), Caspase1, gasdermin D (GSDMD) early stage SA-AKI. Conversely, expression exogenous TIMP2 TIMP2-knockout still protected against damage vitro experiments, using recombinant protein, knockdown inhibited renal tubular cells stimulated by lipopolysaccharide (LPS). Mechanistically, promoted ubiquitination autophagy-dependent degradation NLRP3 increasing intracellular cyclic adenosine monophosphate (cAMP), which mediated through recruiting E3 ligase MARCH7, attenuating downstream pyroptosis, thus alleviating primary cell damage. These results revealed renoprotective extracellular suggested administration could be therapeutic intervention treatment.