The effects of R-75,317 on antiglomerular basement membrane glomerulonephritis in rats |
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Authors: | Masaaki Miyamoto Hiroyuki Koike Toshio Sada Yasuteru Ijima Junichiro Fukushige Norio Nakamura |
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Affiliation: | (1) New Lead Research Laboratories, Sankyo Co., Ltd., 140 Tokyo, Japan;(2) Fermentation Research Laboratories, Sankyo Co., Ltd., 140 Tokyo, Japan;(3) Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140 Tokyo, Japan |
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Abstract: | Platelet-activating factor (PAF) is a potent inflammatory mediator which is released by various inflammatory cells and produced
by certain tissues, including the kidney. PAF has been shown to increase glomerular permeability to protein and to decrease
glomerular filtration rate (GFR) by contracting mesangium. On the basis of these observations, it has been suspected that
PAF may play a role as mediator of glomerular damage in glomerular nephritis. To examine this possibility, we studied the
effects of a specific PAF antagonist, R-75,317, on the development of an experimental model of anti-glomerular basement membrane
(anti-GBM) glomerulonephritis. Glomerulonephritis was initiated by injecting rabbit anti-rat GBM serum into rats. Proteinuria
gradually developed after serum injection, plateaued at week 2, and remained at the high level of week 2 throughout the experimental
period (6 wk). Chronic treatment with R-75,317 (10 mg/kg/day i.p.) tended to delay the onset of proteinuria and significantly
accelerated the recovery phase. Creatinine clearance (Ccr) fell to 40% at week 3. R-75,317 treatment completely prevented
this decline of Ccr. Histological changes in this model (glomerular hypertrophy, proliferation of mesangial matrix and interstitial
fibrosis) were also ameliorated by the R-75,317 treatment. The results suggest that PAF may play a role in the development
of glomerulonephritis and that PAF antagonists could be used in the treatment of human renal disease.
Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl
Ether Lipids, May 1989. |
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