Inhibition of Inducible Nitric Oxide Synthase Alters Thy-1 Glomeruonephritis in Rats

Abstract

Background/Aims: Inducible nitric oxide (NO) synthase (iNOS) generated NO increases in the early phase of Thy-1 glomerulonephritis concurrently with mesangiolysis and reduction in glomerular filtration rate (GFR). Activation of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, is upregulated to allow mesangial cell proliferation which constitutes the repair phase in this model. Antiproliferative high-output NO generation inhibits proproliferative ODC activity, thereby temporally separating the early ‘bactericidal’ phase from the later ‘growth’ repair phase. Methods: Renal function, ODC protein expression, arginine, ornithine, and polyamines by high-performance liquid chromatography, and histological changes were assessed in rats after induction of Thy-1 nephritis with and without NOS inhibition. Results: Thy-1 significantly reduced the GFR relative to untreated controls. Treatment with a nonspecific NOS inhibitor, but not a selective iNOS inhibitor, further decreased the GFR at day 1. This implys a protective role for constitutive NOS in the early phase of this inflammatory model. Selective iNOS inhibition abrogated increased plasma NO₂/NO₃ levels in Thy-1 glomerulonephritis, but did not significantly reduce mesangiolysis. However, inhibition of iNOS did result in significantly more nuclei/glomerulus during the proliferative phase, increasing the hypercellularity component of this disease model. This correlates with increased levels of polyamines, ornithine, and arginine beyond those observed with Thy-1 administration alone. Conclusions: These studies provide evidence that NO generation from different NOS isoforms can be protective in the temporal course of Thy-1 glomerulonephritis. The finding that iNOS attenuates hypercellularity in the repair phase of this inflammatory model adds cautionary insight in the therapeutic use of selective iNOS inhibition in vivo.