Nitric oxide preserves the glomerular protein permeability barrier by antagonizing superoxide

Background. The interaction of nitric oxide with superoxide (O-2(-)) is a major O-2(-) scavenging mechanism that can minimize O-2(-)-mediated oxidative stress. Glomeruli produce both nitric oxide and O-2(-) and generation of both radicals is increased in various forms of glomerular disease. O-2(-) 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 O-2(-) 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. O-2(-) generated after incubation with TNF-alpha or X/XO increased P-alb. This effect was blocked by DETA-NONOate. Conclusion. We demonstrate that nitric oxide protects the glomerular filtration barrier from injury caused by O-2(-) and suggest that inhibition of nitric oxide synthesis could enhance O-2(-)-mediated oxidative injury under pathologic conditions.