Protective effect of a novel and selective inhibitor of inducible nitric oxide synthase on experimental crescentic glomerulonephritis in WKY rats.
BACKGROUND
Nitric oxide (NO) plays important roles in a variety of pathophysiological processes. It has been reported that inducible NO synthase (iNOS) is upregulated in the glomeruli of patients with glomerulonephritis, although there has been no direct evidence that NO generated by iNOS contributes to the progression of glomerulonephritis. ONO-1714, a novel cyclic amidine analog, is a selective inhibitor of iNOS. To elucidate the role of iNOS in the pathogenesis of experimental crescentic glomerulonephritis, we examined the effect of ONO-1714 given to rats with nephrotoxic serum (NTS) nephritis.


METHODS
We induced NTS nephritis in Wistar-Kyoto (WKY) rats. These rats were given ONO-1714 or physiological saline intraperitoneally for 14 days using an osmotic pump after intraperitoneal injection with NTS.


RESULTS
Glomerular expression of iNOS and urinary excretion of NO metabolites (nitrite/nitrate) were increased in rats after injection of NTS. As compared with the control group, ONO-1714 significantly reduced proteinuria, crescent formation, glomerular infiltration of macrophages and urinary excretion of nitrite/nitrate.


CONCLUSIONS
The present results suggest that NO radicals generated by iNOS contribute to the progression of experimental crescentic glomerulonephritis in WKY rats. The selective iNOS inhibitor ONO-1714 may be beneficial for the treatment of crescentic glomerulonephritis.
Ogawa
Daisuke
D
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho, Okayama, Japan.
Shikata
Kenichi
K
Matsuda
Mitsuhiro
M
Okada
Shinichi
S
Usui
Hitomi
H
Wada
Jun
J
Taniguchi
Naoyuki
N
Makino
Hirofumi
H
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005921:Glomerulonephritis / Q000473:pathology* / Q000503:physiopathology*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007678:Kidney Glomerulus / Q000201:enzymology; D009566:Nitrates / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000652:urine; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011921:Rats, Inbred WKY
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat