4-Octyl Itaconate Attenuates LPS-induced Acute Kidney Injury By Activating Nrf2 And Inhibiting STAT3 Signaling

Background: Sepsis-associated acute kidney injury(SA-AKI)is the leading form of acute kidney failure among hospitalized patients.A large number of people are suffer from SA-AKI,and SA-AKI leads to death or chronic kidney disease.Oxidative stress and inflammatory response are involved in this process.4-octyl itaconate(4-OI)is a multitarget itaconate derivative with potent anti-inflammatory action.However,it remains elusive whether and how 4-OI contributes to the regulation of SA-AKI.Methods:We employed a lipopolysaccharide(LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo.In vitro experiments,BUMPT cells,a murine renal tubular cell line,were conducted to examine the effects of 4-OI on inflammation,oxidative stress,and mitophagy.Moreover,STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OIadministrated state.Objective:To investigate the role of 4-OI in tubular injury in SA-AKI and the potential mechanisms.Results:We demonstrate that 4-OI protects against SA-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy.4-OI significantly reduced the levels of Scr,BUN,Ngal m RNA as well as the tubular injury in LPS-induced AKI mice.4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney.4-OI also reduced ROS levels,as well as cleaved caspase-3 and boosted antioxidants such as HO-1,and NQO1 in mice.In addition,the 4-OI treatment significantly promoted mitophagy.Mechanistically,4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro.Molecular docking revealed the binding affinity of 4-OI towards STAT3.ML385,a specific Nrf2 inhibitor,partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and vitro.Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro.Conclusions:These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway,and inactivation of STAT3.Our study identifies 4-OI as a promising pharmacologic for SA-AKI.