Pathophysiologic role of eicosanoids in mesangial cell immune injury.
The pathophysiologic role of thromboxane and of arachidonate 5-lipoxygenation products in mediating changes in glomerular filtration rate (GFR) and renal blood flow (RBF) was investigated in a rat model of mesangial cell immune injury induced by a monoclonal antibody (ER4) directed against the mesangial cell membrane antigen, Thy 1. Following a single intravenous dose of the ER4 antibody acute decrements in GFR and RBF occurred at 1 h and were associated with enhanced glomerular leukocyte infiltration and synthesis of thromboxane A2, 12-HETE and LTB4. Pretreatment of animals with the thromboxane synthase inhibitor, Furegrelate, or the thromboxane receptor antagonist SQ-29,548 ameliorated or completely abolished the decrements in GFR and RBF without reducing glomerular leukocyte infiltration. Pretreatment with the arachidonate 5-lipoxygenase inhibitor MK-886 partially ameliorated the decrements in GFR and RBF, reduced the glomerular leukocyte infiltration and completely inhibited the glomerular LTB4 synthesis. Combined treatment with Furegrelate and MK-886 completely abolished the decrements in GFR and RBF as well as the glomerular synthesis of thromboxane, LTB4 and 12-HETE without altering glomerular leukocyte infiltration. These observations indicate that in mesangial cell immune injury thromboxane A2 and arachidonate 5-lipoxygenation products originating from infiltrating inflammatory cells mediate the decrements in GFR and RBF. Selective inhibition of these eicosanoids could be of benefit in clinical forms of mesangial nephritis.
Lianos
E A
EA
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226.
Bresnahan
B B
BB
Wu
S
S
D000818:Animals; D000911:Antibodies, Monoclonal; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015777:Eicosanoids / Q000502:physiology*; D005231:Fatty Acids, Unsaturated; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D005920:Glomerular Mesangium / Q000276:immunology / Q000293:injuries / Q000503:physiopathology*; D006834:Hydrazines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D002722:Chlorobenzenes
D000911:Antibodies, Monoclonal; D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015777:Eicosanoids; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007211:Indoles; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D017482:Receptors, Thromboxane; D013930:Thromboxane-A Synthase; C060893:MK-886; D002722:Chlorobenzenes; C045749:SQ 29548; C039936:furegrelate