Renal mRNA of PTH-PTHrP receptor, [Ca2+]i and phosphaturic response to PTH in phosphate depletion.
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 elevation of cytosolic calcium ([Ca2+]i) in the cells of these organs. If elevation in [Ca2+]i is indeed the culprit, one should be able to 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 test this hypothesis, we examined the [Ca2+]i and the concentration 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 with verapamil (PD-V, PW-V). To evaluate the effect of a potential rise in [Ca2+]i on urinary phosphate excretion, we also measured the phosphaturic response to PTH and cAMP in all groups of rats after 6 weeks of the dietary intervention. Renal function was normal in all groups of 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 remained low throughout the study. The basal levels of [Ca2+]i in the renal proximal tubular cells were normal after 1 week of PD but rose by the third week of the study and remained elevated by the end of the sixth 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-PTHrP receptor relative to that of the housekeeping gene G3DPH were significantly (p < 0.01) lower in PD rats after 3 and 6 weeks than in the other 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 proximal tubular cells and with down-regulation of PTH-PTHrP receptor in the kidney despite low levels of PTH and normal renal function; normalization 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 elevated blood PTH levels. The improvement in the phosphaturic response to PTH and cAMP in PD-V rats is consistent with the notion that the elevated [Ca2+]i of the renal cell in PD rats may interfere with the coupling of PTH receptor-adenylate cyclase system and/or with the postreceptor events responsible for the inhibition of phosphate reabsorption by these agonists.
Marcinkowski
W
W
Department of Medicine, University of Southern California, School of Medicine, Los Angeles 90033, USA.
Smogorzewski
M
M
Zhang
G
G
Ni
Z
Z
Kedes
L
L
Massry
S G
SG
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010710:Phosphates / Q000172:deficiency* / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics*
D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D000242:Cyclic AMP; D002118:Calcium