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ORIGINAL RESEARCH ARTICLE

Effect of Nitric Oxide Synthase Inhibition on Proteinuria in Glomerular Immune Injury

Prasun K. Datta^*, Mukut Sharma, Pu Duann and Elias A. Lianos^,1

^* Center for Neurovirology/Cancer Biology, Temple University, Philadelphia, Pennsylvania 19122; Nephrology Division, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and Nephrology Division, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901

To whom requests for reprints should be addressed at ¹ Department of Medicine, Division of Nephrology, UMDNJ-Robert Wood Johnson Medical School, 1 RWJ Place, P.O. Box 19, MEB 412, New Brunswick, NJ 08903. E-mail: lianosea{at}umdnj.edu

In glomerular immune injury, the inducible isoform of nitric oxide synthase (iNOS) becomes a major catalyst of NO production. Although iNOS-catalyzed NO production is sustained and can be cytotoxic, iNOS inhibition exacerbates the magnitude of proteinuria that accompanies immune injury. To investigate putative mechanisms of this effect, we assessed changes in glomerular permeability to albumin by using the following two approaches: (i) an in vivo rat model of glomerular immune injury induced by antibody against the glomerular basement membrane (GBM), in which urine albumin excretion was measured under conditions of iNOS inhibition, and (ii) an ex vivo model of isolated rat glomeruli, in which changes in glomerular capillary permeability to albumin were assessed under conditions of NOS inhibition.

In rats with anti-GBM antibody–induced glomerular injury, there was an increase in urine albumin excretion. Treatment with two structurally dissimilar iNOS inhibitors at doses sufficient to decrease urine nitrate and/or nitrite exacerbated proteinuria. In these animals, urine excretion of the isoprostane 8-iso-PGF2 (marker of oxidative stress) was increased. In isolated glomeruli incubated with the NOS inhibitor L-NMMA, the permeability to albumin increased. This effect was reversed by the NO donor DETA NONOate and by the superoxide dismutase mimetic Tempol.

We conclude that NOS-catalyzed NO production is an important mechanism in regulating glomerular permeability to protein. This mechanism involves control of the bioavailability of superoxide.

Key Words: NOS • glomerulus • proteinuria • nephritis