Nrf2 inhibits M1 macrophage polarization to ameliorate renal ischemia–reperfusion injury through antagonizing NF-κB signaling

• DOI: 10.1016/j.intimp.2024.113310
• Publication Date: 2024-10-08T10:39:34Z
• Authors: Hui Han; Yuanyuan Gao; Boxuan Chen; Hongjie Xu; Chenghao Shi; Xiaowu Wang; Yihan Liang; Zhixuan Wu; Ziqiong Wang; Yongheng Bai; Cunzao Wu
• Keywords: Macrophage polarization

Renal ischemia-reperfusion injury (IRI) is a condition that arises from a sudden interruption of the blood flow to the kidney for a period of time followed by restoration of the blood supply. This process contributes to acute kidney injury (AKI), increases morbidity and mortality, and is a major risk factor for chronic kidney disease (CKD). Nuclear factor erythroid-derived 2-like 2 (Nrf2) has been shown to exhibit strong anti-oxidative and anti-inflammatory effects, which are reciprocally regulated by the pro-inflammatory actions of nuclear factor-kappa B (NF-κB) signaling. In this study, we established a model of AKI caused by renal IRI in mice lacking the Nrf2 gene (KO-Nrf2) and mice pre-injected with ML385 (Nrf2 inhibitor). In addition, LPS- or IL-4-induced M1- or M2-type polarized macrophages (RAW264.7), respectively, were also treated with Nrf2 activation and inhibition. The results demonstrated a more pronounced activation of the NF-κB signaling pathway in the Nrf2 inhibition model, accompanied by a more severe inflammatory effect. In cultured macrophages and renal IRI mice, Nrf2 inhibition activated M1 macrophage polarization, thereby increasing the release of proinflammatory cell factors (iNOS and TNF-α) and aggravating renal IRI. Notably, the inhibitory effect of Nrf2 on M1 macrophage polarization was related to the downregulation of the NF-κB signaling pathway activity, resulting in partial relief of renal IRI. Consequently, our findings indicated that Nrf2 inhibits M1 macrophage polarization to ameliorate renal IRI through antagonizing NF-κB signaling. Targeted activation of Nrf2 may be one of the important strategies for renal IRI treatment.