PATHOPHYSIOLOGIC ROLE OF EICOSANOIDS IN MESANGIAL CELL IMMUNE INJURY

The pathophysiologic role of thromboxane and of arachidonate 5-lipoxyg enation products in mediating changes in glomerular filtration rate (G FR) and renal blood flow (RBF) was investigated in a rat model of mesa ngial cell immune injury induced by a monoclonal antibody (ER4) direct ed against the mesangial cell membrane antigen, Thy 1. Following a sin gle intravenous dose of the ER4 antibody acute decrements in GFR and R BF occurred at 1 h and were associated with enhanced glomerular leukoc yte infiltration and synthesis of thromboxane A2, 12-HETE and LTB4. Pr etreatment of animals with the thromboxane synthase inhibitor, Furegre late, or the thromboxane receptor antagonist SQ-29,548 ameliorated or completely abolished the decrements in GFR and RBF without reducing gl omerular 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 complet ely inhibited the glomerular LTB4 synthesis. Combined treatment with F uregrelate and MK-886 completely abolished the decrements in GFR and R BF as well as the glomerular synthesis of thromboxane, LTB4 and 12-HET E without altering glomerular leukocyte infiltration. These observatio ns indicate that in mesangial cell immune injury thromboxane A2 and ar achidonate 5-lipoxygenation products originating from infiltrating inf lammatory cells mediate the decrements in GFR and RBF. Selective inhib ition of these eicosanoids could be of benefit in clinical forms of me sangial nephritis.