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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Superoxide Dismutase Mimetic Preserves the Glomerular Capillary Permeability Barrier to Protein

Department of Medicine/Division of Nephrology, University of Medicine and Dentistry, New Jersey–Robert Wood Johnson Medicine School, New Brunswick, New Jersey (P.D., E.A.L.); Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania (P.K.D.); Divisions of Nephrology (M.S.) and Pediatric Nephrology (C.P.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Antioxidants Research Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts (J.B.B.)

Overproduction of superoxide () occurs in glomerular disease and may overwhelm the capacity of superoxide dismutase (SOD), thereby intensifying oxidant injury by 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- (TNF). 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 TNF has been shown to mediate albuminuria. To increase glomerular capillary permeability to albumin (P_alb) ex vivo, isolated glomeruli were incubated with TNF at concentrations (0.5–4.0 µg/ml) known to stimulate 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 F₂-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, TNF 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 production.

Address correspondence to: Dr. Elias A. Lianos, UMDNJ-Robert Wood Johnson Medical School, Department of Medicine/Division of Nephrology, P.O. Box 19, MEB 412, New Brunswick, NJ 08903-0019. E-mail: lianosea{at}umdnj.edu

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