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Mechanisms of Glomerular Immune Injury: Effects of Antioxidant Treatment

Sriram S. Narsipur^*, Orjan W. Peterson, Robert Smith, Timothy D. Bigby, Sampath Parthasarathy, Francis B. Gabbai, Curtis B. Wilson and Roland C. Blantz

*Division of Nephrology, State University of New York Upstate Medical University, Syracuse, New York; Divisions of Nephrology-Hypertension and Pulmonary-Critical Care and Institute for Biomedical Engineering, University of California, San Diego, School of Medicine and Veterans Affairs Medical Center, La Jolla, California; and Department of Immunology, The Scripps Research Institute, La Jolla, California.

Correspondence to Dr. Sriram S. Narsipur, Nephrology Division, CWB 343, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210; Phone: 315-464-5290; Fax: 315-464-5295;

ABSTRACT. Significant glomerular vasoconstriction and production of reactive oxygen species has been known to occur with exposure to anti–glomerular basement membrane antibody (AGBM-Ab) in the rat model. Previously published studies have demonstrated that such effects can be reduced by therapy with phentolamine, an -adrenergic antagonist. It was hypothesized that antioxidant pretreatment with water-soluble probucol would improve glomerular hemodynamics 60 to 90 min after the administration of AGBM-Ab. These relationships were examined with both in vivo renal micropuncture and in vitro studies in rats. Single-nephron GFR (SNGFR) decreased markedly in untreated rats after AGBM-Ab as a result of afferent and efferent arteriolar vasoconstriction with consequent reductions in nephron plasma flow (SNPF) and decreases in the glomerular ultrafiltration coefficient (LpA). Basal SNGFR was increased, and SNGFR was significantly higher after AGBM-Ab in probucol-treated versus untreated rats. This finding was due solely to higher values for SNPF and prevention of afferent arteriolar constriction. A reduction in LpA after AGBM-Ab was not prevented by probucol treatment. In vitro analyses of glomeruli revealed reduced myeloperoxidase activity in antioxidant-treated rats. Lipoxygenase activity and leukotriene products, however, were not changed by antioxidant therapy, yet vasoconstriction was prevented. H₂O₂ generation before and after formyl-methionyl-leucyl-phenylalanine stimulation was significantly reduced before and after AGBM-Ab in glomeruli harvested from rats that were treated with the antioxidant. Antioxidant therapy in this model of AGBM-Ab injury did not prevent reductions in LpA, an index of glomerular membrane damage, but did prevent afferent arteriolar vasoconstriction. Reactive oxygen species generation was reduced by probucol. The specific mechanisms whereby antioxidant therapy ameliorates glomerular hemodynamic effects will be defined in additional studies and is likely to involve either enhanced vasodilator or diminished vasoconstrictor activity. E-mail narsipur@upstate.edu

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673