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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #193473
Title: SUPEROXIDE DISMUTASE MIMETIC PRESERVES THE GLOMERULAR CAPILLARY PERMABILITY BARRIER TO PROTEIN

Author
item DUANN, PU - UMDNJ
item DATTA, PRASUN - TEMPLE UNIVERSITY
item PAN, CYNTHIA - MEDICAL COLL OF WISCONSIN
item Blumberg, Jeffrey
item SHARMA, MUKUT - MEDICAL COLL OF WISCONSIN
item LIANOS, ELIAS - UMDNJ

Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2005
Publication Date: 3/1/2006
Citation: Duann, P., Datta, P.K., Pan, C., Blumberg, J.B., Sharma, M., Lianos, E.A. 2006. Superoxide dismutase mimetic preserves the glomerular capillary permability barrier to protein. Journal of Pharmacology and Experimental Therapeutics. 316(3):1249-54.

Interpretive Summary: Oxidative stress is the result of an overproduction of reactive oxygen species or “free radicals” and appears to contribute to the decline in many age-related physiological functions and the increased risk for related diseases. Aging is associated with a decline in kidney function that may be determined in part by increases in the urinary excretion of plasma protein. We undertook experiments with kidney cell cultures and a rat model of kidney disease to determine if an antioxidant intervention can help prevent kidney injury and loss of plasma protein. Before testing dietary antioxidants, we examined the effect of a compound, the nitroxide tempol, which mimics the action of the antioxidant enzyme superoxide dismutase. We found that injury to the kidney increased the urinary excretion of plasma protein in close association with an increase in isoprostane, a biomarker of oxidative stress, and that these changes were prevented with treatment by tempol. Thus, future studies employing dietary antioxidants are now warranted.

Technical 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, which 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 anti glomerular basement membrane antibody (anti-GBM), and (2) isolated rat glomeruli in which injury was induced by the cytokine TNFalpha. To induce glomerular immune injury, rats received anti-GBM antibody 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 (Palb) ex vivo, isolated glomeruli were incubated with TNFalpha at concentrations (0.5-4.0 microg/mL) known to stimulate O2(.-) production. Increments in Palb were detected by measuring changes in glomerular volume in response to an applied oncotic gradient. Significant increases in the urine excretion of albumin and F2alpha-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 Palb 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.