RENAL MESSENGER-RNA OF PTH-PTHRP RECEPTOR, [CA2-DEPLETION(](I) AND PHOSPHATURIC RESPONSE TO PTH IN PHOSPHATE)

Available data indicate that the mRNAs of the PTH-PTH-related protein (PTH PTHrP) receptor in the kidney, liver and heart are down-regulated in chronic renal failure (CRF). This is due, in major part, to the el evation of cytosolic calcium ([Ca2+](i)) in the cells of these organs. If elevation in [Ca2+](i) is indeed the culprit, one should be able t o demonstrate down-regulation of the mRNA of the PTH-PTHrP receptor in situations without CRF and with low levels of PTH but with elevated. [Ca2+](i). Such a combination of events occurs in phosphate depletion (PD). To lest this hypothesis, we examined the [Ca2+](i) and the conce ntration of the mRNA of the PTH-PTHrP receptor in the kidneys from 1, 3 and 6 weeks PD, pair-weighed (PW) rats and PD and PW rats treated wi th verapamil (PD-V, PW-V). To evaluate the effect of a potential rise in [Ca2+](i) on urinary phosphate excretion, we also measured the phos phaturic response to PTH and cAMP in all groups of rats after 6 weeks of the dietary intervention. Renal function was normal in all groups o f animals. Blood levels of PTH were significantly (p < 0.01) lower in PD and PD-V after 1 week of PD than in PW and PW-V rats, and they rema ined low throughout the study. The basal levels of [Ca2+](i) in the re nal proximal tubular cells were normal after I week of PD but rose by the third week of the study and remained elevated by the end of the si xth week. These values were significantly (p < 0.01) higher than those in PD-V, PW and PW-V rats. The concentrations of mRNA of the PTH-PTHr P receptor relative to that of the housekeeping gene G3DPH were signif icantly (p < 0.01) lower in PD rats after 3 and 6 weeks than in the ot her three groups of rats. The phosphaturic response to PTH or cAMP was significantly (p < 0.01) greater in PD-V rats than in PD animals. The data show that PD is associated with a rise in [Ca2+](i) of renal pro ximal tubular cells and with down-regulation of PTH-PTHrP receptor in the kidney despite low levels of PTH and normal renal function; normal ization of the concentration of [Ca2+](i) in PD-V rats was associated with normal expression of mRNA of the receptor. These results provide strong support for the proposal that elevated [Ca2+](i) down-regulates the mRNA of the PTH-PTHrP receptor even in the absence of CRF and ele vated blood PTH levels. The improvement in the phosphaturic response t o PTH and cAMP in PD-V rats is consistent with the notion that the ele vated [Ca2+](i) of the renal cell in PD rats may interfere with the co upling of PTH receptor-adenylate cyclase system and/or with the postre ceptor events responsible for the inhibition of phosphate reabsorption by these agonists.