ROLE OF POLYCATIONIC MEDIATORS IN GLOMERULONEPHRITIS

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A number of proliferative glomerulopathies in clinical and experimental settings have a common, episodes of platelet activation, secretion, and glomerular localization of platelet products during the course of the disease processes. Studies are proposed to critically examine the influence of platelet secretory proteins (PSP) on proliferation of mesangial cells in an accelerated model of proliferative glomerulopathy in which mesangial proliferation is induced by Habu snake venom (HSV). Influences of platelet alpha granule proteins (platelet derived growth factor -[PDGF], transforming growth factors alpha and beta [TGF-alpha, TGF-beta] platelet factor 4 (PF4) epidermal growth factor (EGF) and platelet fibronectin (Fn) in the development of mesangial proliferation will be examined by monitoring PSP secretion, glomerular localization of PSP, and cell localization and proliferation. The specificity of PSP involvement in glomerular proliferation will be evaluated by determining the contribution of cells other than platelets that are involved in synthesis and expression of MRNA for PDGF, TGF-alpha and TGF-beta and their translated proteins. Antibodies raised against specific PSP or receptors will be used to neutralize and interfere with PSP-mesangial cell interaction and modulate proliferative lesions. PDGF, TGF-alpha, TGF-beta, PF4, and platelet Fn will be verified as growth factors in vivo by recreation of the sequence of events leading to proliferative by infusion back into kidneys of HSV-treated rats, in which platelets have been depleted by anti-platelet serum. Studies will examine specific mechanisms of action (migration, mitogenesis and neutralization of a growth inhibiting substance, heparin) by specific PSP in culture. These studies will provide valuable information regarding PSP-mesangial interactions in progressive, proliferative glomerulonephritis.