Irg1-itaconate axis protects against acute kidney injury via activation of Nrf2.

Acute kidney injury (AKI) is a common clinical implication with increased tissue damage, uncontrolled immune responses, and risk of mortality, in which ischemia-reperfusion injury (IRI) is one of the leading causes. As critical role for metabolic remodeling in inflammation, Irg1-itaconate axis has received much attention for its immunomodulation in the control of the inflammation. However, its role in the AKI and IRI remains unknown. Here, we found that Irg1 expression was negatively correlated with the expression of inflammatory cytokines during ischemia-reperfusion injury. And Irg1 deficiency promotes renal inflammation and ischemia-reperfusion injury in vivo. Itaconate treatment promoted the survival of WT mice from lethal ischemia and protected against renal IRI and systemic inflammation. Mechanistically, dimethyl itaconate protected renal cells from oxidative stress and prevented macrophage activation by enhancing the translocation of Nrf2 into the nuclei. Our study highlighted the importance of the Irg1-itaconate axis in the protecting against ischemia-reperfusion injury and acute kidney injury, providing potential therapeutic targets to control AKI.