NOVEL INFLAMMATORY MEDIATORS IN GLOMERULONEPHRITIS

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The proposed work aims to: 1) employ in vitro biochemical studies in order to investigate the synthesis of vasoactive (prostaglandins, thromboxanes) and proinflammatory (hydroxyeicosatetraenoic acids, leukotrienes, and alkyl ether glycerophospholipids) mediators by cultured rat glomerular cells in response to defined immunologic reactants and 2) employ in vivo physiologic studies (renal clearance and micropuncture) to evaluate the effects of pharmacologic inhibition of the synthesis or pharmacologic antagonism of the action of the aforementioned mediators on renal hemodynamic perturbations occurring following induction of experimental glomerulonephritis in the rat. The immunologic reactants to be tested in vitro are: antibodies against the Heymann antigen present in glomerular epithelial cells, antibody against rat thymocytes and reactive with Thy-l-like antigens present on rat mesangial cells, the complement components C3a and C5a, the membrane attack complex C5b-9 and the platelet derived cationic proteins, platelet factor-4 and platelet derived growth factor. When these reactants are deposited in glomeruli during the evolution of glomerular immune injury, they can induce hemodynamic perturbations or mediate glomerular cell injury. Moreover, when they bind to glomerular cells in vitro, an enhanced biosynthetic activity and mediator synthesis occurs. Whereas the in vitro studies aim to identify the glomerular cell type(s) capable of mediator synthesis in response to these reactants/agonists, the key purpose of the physiological studies is to prove or disprove that mediator synthesis in vivo is associated with renal hemodynamic perturbations in three models of experimental antibody induced glomerulonephritis (GN): nephrotoxic serum GN or anti-GBM disease, passive Heymann nephritis and anti- thymocyte serum (anti-thy 1 antibody) induced glomerulopathy. In these models well defined glomerular hemodynamic perturbations occur following antibody administration. Moreover, the glomerular synthesis of eicosanoids and alkyl ether phospholipids is enhanced. The proposed in vivo and in vitro studies, therefore, complement each other and it is anticipated that the information accrued will provide evidence that biochemical and physiological events occurring in glomerular immune injury are interrelated and will provide the groundwork for specific intervention.