Superoxide dismutase mimetic preserves the glomerular capillary permeability barrier to protein.

Overproduction of superoxide (O2*) occurs in glomerular disease and may overwhelm the capacity of superoxide dismutase (SOD), thereby intensifying oxidant injury by O2* and related radical species that disrupt the glomerular capillary permeability barrier to protein. We examined the efficacy of the SOD mimetic tempol in preserving glomerular permeability to protein using 1) a rat model of glomerular immune injury induced by an antiglomerular basement membrane antibody (anti-GBM), and 2) isolated rat glomeruli in which injury was induced by the cytokine tumor necrosis factor-alpha (TNFalpha). To induce glomerular immune injury, rats received anti-GBM using a protocol that results in prominent infiltration of glomeruli by macrophages and in which macrophage-derived TNFalpha has been shown to mediate albuminuria. To increase glomerular capillary permeability to albumin (P(alb)) ex vivo, isolated glomeruli were incubated with TNFalpha at concentrations (0.5-4.0 microg/ml) known to stimulate O2* production. Increments in P(alb) were detected by measuring changes in glomerular volume in response to an applied oncotic gradient. Significant increases in the urine excretion of albumin and F(2alpha)-isoprostane were observed in rats with glomerular immune injury without a significant change in systolic blood pressure. Tempol treatment significantly reduced urine isoprostane and albumin excretion. In isolated glomeruli, TNFalpha increased P(alb) and tempol abrogated this effect, both in a dose-dependent manner. These observations indicate that SOD mimetics can preserve the glomerular permeability barrier to protein under conditions of oxidative stress from O2* production.