Fisetin protects against high fat diet-induced nephropathy by inhibiting inflammation and oxidative stress via the blockage of iRhom2/NF-κB signaling.

Promoted inflammation enhances the development of nephropathy in obesity. Fisetin (3,3',4',7-tetrahydroxyflavone, FIS) is a naturally occurring dietary flavonoid, and exhibits anti-inflammatory and anti-oxidative properties. Inactive rhomboid protein 2 (iRhom2), an inactive member of the rhomboid intramembrane proteinase family, is an essential inflammation-associated regulator. Here, we attempted to investigate the protective mechanisms of FIS against high fat diet (HFD)-induced nephropathy, with particular focus on iRhom2. We found that HFD induced systematic and renal pro-inflammatory cytokine production. Furthermore, iRhom2 expression was markedly elevated in kidney of HFD-fed mice, and in PAL-incubated macrophages, accompanied with high phosphorylation of NF-κB. Significant oxidative stress was observed in kidney of HFD-fed mice through suppressing Nrf-2/HO-1 signaling. Moreover, activation of iRhom2/NF-κB signaling and oxidative stress by PAL was detected in macrophages, which were effectively reversed by FIS. Importantly, we showed that iRhom2 knockdown significantly abrogated the ability of FIS to restrain inflammation and oxidative stress induced by PAL in macrophages, indicating that iRhom2 might be a potential therapeutic target for FIS during nephropathy treatment. Together, these results revealed that FIS could mitigate HFD-induced renal injury by regulating iRhom2/NF-κB and Nrf-2/HO-1 signaling pathways.