title: Inhibition of inducible nitric oxide synthase alters Thy-1 glomeruonephritis in rats.
abstract: OBJECTIVE
  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 NO(2)/NO(3) 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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Stein Institute for Research on Aging, University of California, San Diego 92161, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Satriano
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Lortie
authors.forename: Shunji
authors.initials: S
authors.lastname: Ishizuka
authors.forename: José M
authors.initials: JM
authors.lastname: Valdivielso
authors.forename: Beth
authors.initials: B
authors.lastname: Friedman
authors.forename: Karen A
authors.initials: KA
authors.lastname: Munger
mesh_terms: D000818:Animals; D005921:Glomerulonephritis / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018800:Thy-1 Antigens / Q000378:metabolism*
chemical_list: D018800:Thy-1 Antigens; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat