It is our long range goal to learn about the behavior of kidney tubules in health and in disease, with the objective of improving diagnosis, management and prevention of human tubulointerstitial nephritides. We have described an injury of tubules, occurring during the natural course of Heymann nephritis (HN) in rats, that is unique in the selectivity with which it affects proximal segments of kidney tubules. We have identified 4 discrete stages of HN with respect to immunopathology of proximal tubules (PT). Damage is mediated by autoantibodies to the brush border (BB) of PT cells. This animal model offers us the opportunity to evaluate the relationship of function to morphology in PT. We plan to measure overall kidney physiology in different stages of HN. In addition, the behavior or individual nephrons will be assessed by micropuncture techniques. All observations of pathophysiology will be correlated with kidney immunopathology, evaluated by means of light, immunofluorescence and electron microscopy. An assessment of protein reabsorption, using the histochemical tracer, horseradish peroxidase, will complement studies of physiology. By using peroxidase molecules that differ in net charge we will be able to detect alterations in the charge selectivity of damaged PT epithelium. Taken together, these experiments will alllow us to document the functional response of the whole kidney, individual nephrons, individual tubule segments and individual tubule cells to selective damage of PT. With this model we will also be able to characterize morphological aspects of the response of the kidney to PT injury. We plan to study quantitative aspects of epithelial cell proliferation in different stages of HN and in passive transfer experiments. Techniques of light microscopy and autoradiography will be used to determine the fate of newly divided cells. Finally, we propose to analyze one aspect of the mechanism by which autoantibodies to membrane antigens may damage cells in vivo. The role of complement will be tested by passive transfer of antibodies to complement depleted recipients and by microinfusion of antibodies, with and without complement, directly into normal PT. These studies will allow us to assess the impact of selective PT damage on the kidney. We hope to identify criteria of function and histology that will facilitate the interpretation of PT damage in man. In addition we anticipate that we will come to understand better the normal function of PT.
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