title: 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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Macconi
authors.forename: A
authors.initials: A
authors.lastname: Benigni
authors.forename: M
authors.initials: M
authors.lastname: Morigi
authors.forename: A
authors.initials: A
authors.lastname: Ubiali
authors.forename: S
authors.initials: S
authors.lastname: Orisio
authors.forename: M
authors.initials: M
authors.lastname: Livio
authors.forename: N
authors.initials: N
authors.lastname: Perico
authors.forename: T
authors.initials: T
authors.lastname: Bertani
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
authors.forename: C
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins / Q000096:biosynthesis; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled; D013928:Thromboxane A2 / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D001095:Arachidonic Acids; D005663:Furans; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D016718:Arachidonic Acid; D013928:Thromboxane A2; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; D013930:Thromboxane-A Synthase