title: Superoxide dismutase mimetic preserves the glomerular capillary permeability barrier to protein.
abstract: 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.
authors.affiliation: Department of Medicine/Division of Nephrology, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medicine School, New Brunswick, NJ 08903-0019, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Duann
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Datta
authors.forename: Cynthia
authors.initials: C
authors.lastname: Pan
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Blumberg
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.forename: Elias A
authors.initials: EA
authors.lastname: Lianos
mesh_terms: D000818:Animals; D000906:Antibodies / Q000633:toxicity; D001323:Autoantibodies; D002199:Capillary Permeability / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D011917:Rats, Inbred Lew; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D003497:Cyclic N-Oxides; D011506:Proteins; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; C051951:antiglomerular basement membrane antibody; D013481:Superoxides; C001803:tempol