Dimethyl fumarate ameliorated pyroptosis in contrast-induced acute renal injury by regulating endoplasmic reticulum stress and JAK2-STAT3 pathway.

BACKGROUND

Inflammation and oxidative stress are important pathological processes of contrast-induced acute renal injury (CIAKI). This study explored whether DMF had therapeutic effects and investigated the underlying mechanism in CIAKI.

METHODS

A CIAKI animal model was established in C57BL/6J mice with iohexol, and DMF was used as an intervention. In vitro, HK-2 cells were treated with iohexol and DMF. RNA-seq analysis was performed on the renal tissue of the mice. Protein-protein interaction (PPI), and enrichment analysis were subsequently conducted. In addition, endoplasmic reticulum stress (ERS) activation and STAT3 inhibition were used to study the relationships among ERS, the JAK2-STAT3 pathway and pyroptosis.

RESULTS

DMF improved the renal function of CIAKI model mice. Enrichment analysis revealed that the differentially expressed genes (DEGs) were enriched mostly in the acute phase response and the JAK-STAT pathway. The results revealed that inflammation, ERS and pyroptosis increased in the CIAKI group but decreased after DMF treatment. Further study revealed that the JAK2-STAT3 pathway was overactivated in vivo and in vitro and that DMF inhibited the JAK2-STAT3 pathway. In addition, ERS activation could increase the JAK2-STAT3 pathway and pyroptosis, while STAT3 knockdown could reverse pyroptosis, indicating that ERS could activate the JAK2-STAT3 pathway, further triggering pyroptosis. DMF ameliorated pyroptosis through regulating ERS and the JAK2-STAT3 pathway in CIAKI.

CONCLUSION

This study demonstrated that DMF had renoprotective effects on CIAKI. DMF ameliorated pyroptosis through the inhibition of ERS and the JAK2-STAT3 pathway.