Increased Glomerular Production of Endothelin-1 in Minimal Change Disease is Mediated by Reactive Oxygen Species in vivo and in vitro

Both reactive oxygen species (ROS) and endothelin-1 (ET-1) have been implicated in the pathophysiology of minimal change disease (MCD). The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in MCD, we examined the in vitro and in vivo effects of ROS donors and scavengers on the glomerular production of ET-1 by MCD rats that were induced by puromycin aminonucleoside. For in vitro study, the glomeruli were isolated from MCD and normal rats using a sieving method. The ET-1 was measured by radioimmunoassay and ET-1 mRNA expression was measured by Northern blot analysis. The results demonstrated that the basal production of ET-1 and superoxide were higher in MCD glomeruli than in normal glomeruli in vitro. There was a positive correlation between the production of ET-1 and superoxide in MCD but not in control glomeruli. The basal ET-1 production were markedly attenuate dby ROS scavengers including superoxide dismutase, catalase, dimethylsulfoxide and deferroxamine in MCD glomeruli, and the golmerular ET-1 mRNA expression was equally supperessed. Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1 generation by both MCD and normal glomeruli. The in vivo study demonstrated that when MCD rats were injected daily with superoxide dismutase or catalase after PAN injection, the basal production of ET-1 was markedly attenuated. These results indicate that endogenously or exogenously derived ROS can enhance ET-1 production by MCD rat glomeruli, and that ROS scavengers suppress ET-1 production both in vitro and in vivio, indicating the ROS mediate the glomerular production of ET-1 in MCD.