In this proposal, mechanisms underlying progressive glomerular damage in chronic renal diseases will be investigated in animals, specifically in various rat models. To explore triggering and continuing mechanisms common, as well as unique, to various forms of disease processes, several models will be subjected to investigation. To accomplish our goal we will use two types of experimental approaches: One is to assess correlation at the single glomerular level between early patterns of glomerular hemodynamic and biosynthetic patterns vs late glomerular structure. For this purpose, we feel it essential to use the recently developed method of serial micropuncture assessment in the same nephron together with histological analysis made on the same nephron. This method will allow us to examine this correlation even in highly heterogenous nephrons characteristic of chronic renal diseases, and to monitor various parameters throughout the disease course. Various histological and histochemical studies used to define the substructural constituents of damaged glomeruli are expected to provide an opportunity to examine the function-structure relationship in depth. The second approach is designed to supplement findings from the first approach by imposing suspect substances and factors on normal glomeruli, or by altering diseased glomeruli both mechanically and chemically. These include: examination of the influence of mitogenic substances on normal mesangial cells cultured in vitro, and study of the effect of normalization of abnormal glomerular hemodynamics on glomerular macromolecular transport. In addition, these two approaches will be employed to investigate the mechanisms involved in the modification of the disease process induced by several experimental manipulations, e.g., special dietary regimens. Such manipulations will hopefully obtain further insight into the biological mechanisms underlying the progression of glomerular damages.
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