We have recently discovered the presence of the N-rnethyI-D-aspartate (NMDA) receptorin the rat kidney. This receptor functions as a calcium channel and has been extensively examined in the brain. Studies proposed in this application will test the Hypothesis that: The NMDA receptor has an important functional role in the kidney, which is independent from its central nervous action as an amino acid neurotransmitter receptor. To test this hypothesis, the following Specific Aims will be addressed. 1) Characterization and localization of the NMDA receptors in the kidney. By using immunohistochemical localization, Western blot analysis, Northern blot and RT-PCR techniques, we will characterize the NMDA receptor(s) present in the rat kidney. By determining the specific sub-type and location of the receptor, we can make inferences on its possible function(s). 2) Activation of the NMDA receptor and regulation of function in the kidney. Using NMDA receptor antagonists and agonists in the rat, we will evaluate changes in renal function such as renal hemodynamics, sodium and amino acid handling. In addition, by using cultured cell lines and primary cultures, we will examine receptor regulation and function at the cellular level. These studies will determine the baseline function of the NMDA receptor, and provide evidence on possible endogenous agonists of NMDA in the kidney. 3) Physiologic regulation and control of the NMDA receptor in the kidney. These studies will utilize whole animal physiology, and cellular and molecular techniques. We will measure the effects of dietary protein and amino acid manipulations nitricoxide/angiotensin system contributions, hypertrophy and contribution of polyamines to the renal NMDA receptor(s). These studies will determine how the NMDA receptor may be regulated and contribute to the long-term regulation of renal function.These studies will provide valuable information regarding the basic biology of this calcium channel in the kidney and may lead to treatment of renal diseases that are influenced by actions of the NMDA receptor.
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