Chronic glomerulonephritis (GN) remains the most common cause of end stage renal disease in the U.S. The specific mechanisms that induce and cause progressive glomerular injury in GN in man are poorly understood. The specific localization of immune proteins (immunoglobulins, complement) in glomeruli and the responses of cells in the glomerulus strongly influence the type and extent of renal disease. Circulating inflammatory cells are a feature of most forms of immune-mediated GN and glomerular cell-leukocyte interactions also influence the process of GN in man. Specific glomerular cell responses can be defined in vitro. In a series of preliminary studies in our laboratory, human glomerular capillary endothelial cells (GCEC) and mesangial cells (MC) have been grown separately in vitro to assess the responses of glomerular capillary cells in immune complexes (IC) separate IC components and cytokines. MC, GCEC and other endothelial cells have been shown to release substances that activate leukocytes and promote leukocyte adherence. The human MC and GCEC also release prostacyclin, thromboxane A2 and fibronectin in differing amounts upon exposure to immunoproteins. This proposal aims to further characterize in vitro the responses of GCEC and MC to IC complement components and cytokines. Changes induced in the cells by these components will be assessed by phase microscopy and cell proliferation assays. Cell viability will be determined by cytotoxicity assay. The promotion of specific leukocyte adherence will be defined. The release of soluble mediators of leukocyte activation, adherence, chemotaxis and chemiluminescence will be assayed and the secretion of immunologically active compounds such as prostaglandins, fibronectin, leukotriene B4, interleukin-1 and superoxides determined. Studies designed to investigate the mechanisms responsible for the responses of the GCEC and MC will be performed. The cell culture techniques described in this proposal offer a unique opportunity to probe the mechanisms of normal and altered glomerular cell behavior using human glomerular endothelial and mesangial cells. These studies should provide new insights into therapeutic modalities for the prevention and treatment of GN in man.
| Mahan, J D; Hebert, L A; McAllister, C et al. (1993) Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate. Kidney Int 44:716-25 |
