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Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials.

Abstract
Previous studies have shown that platelet-activating factor (PAF) receptor blocking has a protective effect on rabbit nephrotoxic nephritis (NTN). We examined whether arachidonic acid (AA) metabolism is altered in NTN and whether a PAF receptor antagonist has any influence on such changes. Rabbits injected with anti-glomerular basement membrane antiserum in the heterologous phase had a markedly increased glomerular thromboxane B2 (TxB2) production level, whereas no changes have been detected in glomerular 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2). During the autologous phase of the disease, the glomerular TxB2 level was even higher than in the heterologous phase. The level of 6-keto-PGF1 alpha was significantly lower than normal, and the level of PGE2 was unchanged in respect to the basal values. The use of L-652,731 (a specific PAF receptor antagonist) reversed the abnormal generation of AA metabolites at glomerular level both in the heterologous and autologous phase of the disease. The effect of L-652,731 on AA metabolism is likely to be an indirect result of the PAF receptor blocking, because L-652,731 given to normal rabbits had no direct effect on glomerular AA metabolism. To assess whether the beneficial effect of L-652,731 in NTN is at least in part mediated by its capability of suppressing the excessive intrarenal synthesis of thromboxane A2 (TxA2), we compared the effect of L-652,731 with that of a selective TxA2-synthase inhibitor (FCE-22178). FCE-22178 ameliorated the morphologic expression of rabbit NTN and reduced function deterioration. The protective effect of L-652,731 on proteinuria in the autologous phase and on glomerular filtration rate in both phases was superior to that of FCE-22178. We conclude that an excessive intraglomerular synthesis of TxA2 occurs in rabbit NTN that can play a role in renal function deterioration. Both a specific PAF receptor antagonist and a TxA2-synthase inhibitor reduced the exaggerated TxA2 synthesis and favorably influenced the evolution of the disease.
AuthorsD Macconi, A Benigni, M Morigi, A Ubiali, S Orisio, M Livio, N Perico, T Bertani, G Remuzzi, C Patrono
JournalThe Journal of laboratory and clinical medicine (J Lab Clin Med) Vol. 113 Issue 5 Pg. 549-60 (May 1989) ISSN: 0022-2143 [Print] United States
PMID2541212 (Publication Type: Journal Article)
Chemical References
  • Arachidonic Acids
  • Furans
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Prostaglandins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor
  • Arachidonic Acid
  • Thromboxane A2
  • 2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran
  • Thromboxane-A Synthase
Topics
  • Animals
  • Arachidonic Acid
  • Arachidonic Acids (metabolism)
  • Furans (pharmacology)
  • Glomerulonephritis (drug therapy, etiology)
  • Kidney (drug effects, pathology, physiopathology)
  • Kidney Glomerulus (metabolism)
  • Male
  • Platelet Activating Factor (antagonists & inhibitors, physiology)
  • Platelet Aggregation (drug effects)
  • Platelet Membrane Glycoproteins
  • Prostaglandins (biosynthesis)
  • Rabbits
  • Receptors, Cell Surface (drug effects)
  • Receptors, G-Protein-Coupled
  • Thromboxane A2 (physiology)
  • Thromboxane-A Synthase (antagonists & inhibitors)

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