Effects of a novel elastase inhibitor, ONO-5046, on nephrotoxic serum nephritis in rats.
ONO-5046 is a potent, specific and intravenously active inhibitor of neutrophil elastase. To examine the role of elastase in glomerulonephritis, we tested the effects of ONO-5046 on nephrotoxic serum (NTS) nephritis in a rat model of the disease in humans. Rats were administered ONO-5046 or phosphate-buffered saline (PBS) intraperitoneally 24 hours prior to injection of NTS, and they were then given equal doses of ONO-5046 or PBS three hours and 1, 2, 3, 4, 5 and 6 days later. Compared with the control groups, ONO-5046 significantly reduced proteinuria and hematuria, and suppressed the formation of crescentic glomeruli in a dose-dependent manner. Our results suggest that neutrophil elastase participates in NTS nephritis by degrading glomerular basement membrane proteins, and that the elastase inhibitor, ONO-5046, suppresses crescentic formation and glomerular injury caused by elastase.
Suzuki
S
S
Department of Clinical and Laboratory Medicine, Fukui Medical University, Japan. SSUZUKI@fmsrsa.fukui-med.ac.jp
Gejyo
F
F
Kuroda
T
T
Kazama
J J
JJ
Imai
N
N
Kimura
H
H
Arakawa
M
M
D000818:Animals; D000910:Antibodies, Heterophile / Q000008:administration & dosage; D001485:Basement Membrane / Q000276:immunology; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006417:Hematuria / Q000517:prevention & control; D006801:Humans; D007678:Kidney Glomerulus / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D009393:Nephritis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011921:Rats, Inbred WKY; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D000910:Antibodies, Heterophile; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine