Mechanisms of glomerular immune injury: effects of antioxidant treatment.
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 alpha-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. H(2)O(2) 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.
Narsipur
Sriram S
SS
Division of Nephrology, CWB 343, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. narsipur@upstate.edu
Peterson
Orjan W
OW
Smith
Robert
R
Bigby
Timothy D
TD
Parthasarathy
Sampath
S
Gabbai
Francis B
FB
Wilson
Curtis B
CB
Blantz
Roland C
RC
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001485:Basement Membrane / Q000276:immunology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology* / Q000293:injuries*; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009399:Nephrons / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species; D014867:Water / Q000494:pharmacology
D000906:Antibodies; D000975:Antioxidants; D017382:Reactive Oxygen Species; D014867:Water; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006861:Hydrogen Peroxide; D009195:Peroxidase; D008084:Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D011341:Probucol