The objective is to establish the mechanism for the resistance to the phosphaturic effects of hormones during phosphate deprivation. The general hypothesis to be tested is that the site of regulation of phosphate excretion shifts from the proximal convoluted tubule in normal phosphate balance to the pars recta and distal nephron segments in phosphate conservation. The hypothesis that the pars recta segment of the proximal tubule selectively contributes to the resistance to the phosphaturic effect of parathyroid hormone will be tested in rats fed a low phosphate diet. The mechanisms of decreased hormonal response will be explored utilizing cAMP analogs which will be infused into the renal interstitium utilizing a newly developed implanted capsule method. The possibility that the response of the adenylate cyclase system to parathyroid hormone is selectively blunted in the pars recta segment of the proximal tubule will be tested in specific microdissected tubules from rats fed a low phosphate diet. The role of the distal convoluted tubule will also be evaluated utilizing micropuncture and in vivo microperfusion techniques. The general principles of adaptation will be extended by evaluating the effects of calcitonin, another hormone which is phosphaturic in the rat. The major significance of these studies is the potential for demonstration of the emergence of the pars recta and distal nephron segments as major sites of regulation of phosphate excretion during phosphate conservation by the kidney. These studies will allow interpretation of changes in phosphate exretion seen at the level of the whole kidney and focus attention on appropriate nephron segments for studies at the cellular level. The insights gained have implications for clinical syndromes characterized by phosphate depletion.
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