With a decrease in renal mass due either to renal ablation or to transplantation, compensatory responses occur that enable the residual nephrons to maintain water and solute homeostasis. These responses eventuate in a number of structural and functional alterations both beneficial such as increased single nephron glomerular filtration rate (SNGFR) and increased nephron mass, and deleterious such as eventual glomerular sclerosis. The mediators of these compensatory growth responses have not been well characterized in the kidney. However, growth factors including EGF, which is one of the most biologically potent growth factors, have been demonstrated to mediate cell proliferation and hypertrophy in a variety of epithelial and mesenchymal cells. Also, the mRNA for the EGF precursor, prepro EGF, has been found in high concentrations in the kidney along with high levels of EGF in the urine. Besides its growth promoting effects, EGF also mediates arachidonate metabolism and smooth muscle contraction, two functions of great potential importance in the pathophysiology of the rejecting transplant or remnant kidney. We propose to study the role of EGF as a mediator of both the physiologic and pathophysiologic responses to a reduction in renal mass. These studies will pursue complementary lines of investigation that will both help to elucidate the whole kidney localization of sites of EGF production and effects and will characterize the effects of EGF specifically on the glomerulus, an important site in the response to renal ablation and transplantation. We will utilize immunohistocytochemical localization and in situ hybridization to identify (a) EGF receptors, (b) prepro EGF and (c) lipocortin, a putative intracellular mediator of the actions of EGF, in normal, remnant, and transplant kidneys. In addition, we shall examine the effects of EGF on growth, intracellular pH, calcium concentration, contractility, arachidonate metabolism and matrix formation in control, remnant and transplant glomeruli as well as cultured mesangial cells.
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