Nitric oxide preserves the glomerular protein permeability barrier by antagonizing superoxide.
BACKGROUND
The interaction of nitric oxide with superoxide (O2-) is a major O2- scavenging mechanism that can minimize O2 (-)-mediated oxidative stress. Glomeruli produce both nitric oxide and O2- and generation of both radicals is increased in various forms of glomerular disease. O2- increases glomerular capillary permeability to albumin (P(alb)). The present studies tested the hypothesis that nitric oxide opposes this effect, thereby preserving the glomerular protein permeability barrier.


METHODS
P(alb) was determined in isolated rat glomeruli by measuring the change in glomerular volume in response to an experimental oncotic gradient. Changes in P(alb) in response to O2- generated by tumor necrosis factor-alpha (TNF-alpha) or xanthine/xanthine oxidase (X/XO) was assessed under conditions of nitric oxide depletion and repletion.


RESULTS
Incubation of rat glomeruli with the nitric oxide synthase (NOS) inhibitor L-N(G)-monomethyl arginine (L-NMMA) increased P(alb.) This effect was reversed by the nitric oxide donor diethylenetriamine NONOate (DETA-NONOate) and by the superoxide dismutase (SOD) mimetic Tempol. O2- generated after incubation with TNF-alpha or X/XO increased P(alb). This effect was blocked by DETA-NONOate.


CONCLUSIONS
We demonstrate that nitric oxide protects the glomerular filtration barrier from injury caused by O2- and suggest that inhibition of nitric oxide synthesis could enhance O2(-)-mediated oxidative injury under pathologic conditions.
Sharma
Mukut
M
Medical College of Wisconsin, Department of Medicine, Division of Nephrology, Milwaukee, WI 53226, USA. msharma@mcw.edu
McCarthy
Ellen T
ET
Savin
Virginia J
VJ
Lianos
Elias A
EA
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000418:Albumins; D000975:Antioxidants; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; C001803:tempol