TRIM44 alleviates renal ischemia-reperfusion injury by inhibiting pyroptosis through the NLRP3 pathway.

Abstract

Background: Renal ischemia-reperfusion injury (IRI) is a prevailing manifestation of acute kidney injury (AKI) with limited treatment options. TRIM44 has emerged as a possible target for treatment due to its regulatory function in inflammatory pathways.

Methods: In vivo and in vitro models were employed to ascertain the TRIM44 impact on renal IRI. In vivo, we induced IRI in mice and assessed histological changes, oxidative stress markers, and pyroptosis-related proteins. In vitro, we subjected renal cells to hypoxia/reoxygenation (H/R) and manipulated TRIM44 expression to evaluate its effects on cell viability and pyroptosis.

Results: IRI significantly increased inflammation, oxidative stress, and pyroptosis in both animal and cell models, evidenced by elevated cleaved caspase-1, GSDMD-N, and IL-1β/-18 levels. IRI conditions experienced a mitigated TRIM44 expression. Overexpression of TRIM44 in renal cells reduced pyroptosis, as shown by decreased levels of pyroptosis-related proteins and inflammatory cytokines and improved cell viability. Mechanistically, TRIM44 inhibited the NLRP3 inflammasome, as evidenced with reduced NLRP3 and cleaved caspase-1 levels upon TRIM44 overexpression and NLRP3 inhibition. In vivo, intravenous administration of TRIM44-expressing adenovirus post-IRI ameliorated renal damage, as reported with mitigated serum creatinine and blood urea nitrogen levels.

Conclusion: TRIM44 protects against renal IRI by inhibiting pyroptosis via the NLRP3 pathway, suggesting its potential to be targeted therapeutically for treating AKI.