The overall objective of this application is to determine the mechanisms of renal phosphate regulation. The hypothesis to be tested is that dopamine and serotonin are counter regulatory paracrine substances that interact with PTH to modulate phosphate reabsorption by the proximal tubule. The effects of endogenous intrarenal dopamine and serotonin synthesis on phosphate excretion will be determined by infusion of selective dopamine and serotonin receptor antagonists in the absence and presence of PTH in rats fed low or high phosphate diets and in rats with a remnant kidney. The proposal that dopamine-induced increases in cAMP regulates phosphate transport predominantly in the proximal convoluted tubule whereas PTH has effects in both the proximal convoluted and straight tubules will be tested. The nephron subsegments of inhibition of phosphate reabsorption by dopamine and enhanced phosphate reabsorption by serotonin as well as their interaction with PTH will be determined in vivo by micropuncture studies. The cellular mechanisms that mediate the changes in phosphate transport by dopamine and serotonin will be studied in proximal nephron subsegments by the determination of cAMP, protein kinase A, and cAMP phosphodiesterase (PDE) isozyme activities in microdissected proximal convoluted and proximal straight tubules in the absence and presence of PTH. The postulate that the cAMP generated in response to dopamine and PTH, may be linked to distinct PDE isozymes and constitute parallel cellular signaling pathways, one for endocrine and one for paracrine stimulus, will be studied. The mechanism whereby dopamine potentiates and serotonin blunts the effect of PTH in the same cell, will be determined in transport studies in OK cells, where the same components of the signaling systems can be simultaneously monitored. These studies have the potential to further define important paracrine roles for dopamine and serotonin on phosphate reabsorption by the proximal tubule with implications for phosphate homeostasis in renal failure.
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