PARATHYROIDECTOMY DOES NOT PREVENT THE RENAL PTH/PTHRP RECEPTOR DOWN-REGULATION IN UREMIC RATS

In a recent study we demonstrated that the PTH/PTHrP receptor (PTH-R) mRNA was markedly down-regulated in the remnant kidney of uremic rats with severe secondary hyperparathyroidism. Among the factors potentially implicated in this downregulation, to date only PTH has been demonstrated to modulate PTH-R expression. Here, we examined the effect of thyroparathyroidectomy (TPTX) on the renal expression of PTH-R in rats with normal renal function or with chronic renal failure (CRF) induced by 5/6 nephrectomy. Four groups of rats were studied: control, TPTX, CRF, and CRF+TPTX. Moderate-degree renal failure was documented by mean(+/- SD) creatinine clearances (mu l/min/100 g body wt) of 259 +/- 40 and 212 +/- 45 in CRF and CRF+TPTX rats, compared with 646 +/- 123 and 511 +/- 156 in control and TPTX rats, respectively. Plasma phosphorus, calcitriol, and ionized calcium were significantly lower in CRF and CRF+TPTX than in control animals. Plasma ionized calcium and calcitriol were also lower in TPTX than in control rats. Plasma PTH levels (pg/ml) were increased in CRF rats (41.8 +/- 29.4), and markedly decreased in TPTX (10.1 +/- 7.8) and CRFfTPTX (8.0 +/- 3.8) rats compared with control rats (21.7 +/- 7.5). Northern blot analysis showed that the level of the steady-state PTH-R mRNA in the kidney of CRF and CRFS-TPTX rats was markedly decreased compared with that of control rats, the ratios of PTH-R mRNA/beta-actin mRNA being 0.28 +/- 0.04 and 0.27 +/- 0.03 versus 0.54 +/- 0.05, respectively. The PTH-R mRNA expression was also found decreased in bone tissue from two uremic animals compared with control rats: 0.59 versus 0.78, respectively. No change was observed in the renal PTH-R mRNA level in TPTX animals. There was also no change in the PTH-R mRNA expression in the liver of uremic rats. The expression of the PTHrP mRNA was comparable in the kidney of control and CRF animals. CRF and CRF+TPTX rats showed a similarly reduced PTH-sensitive adenylyl cyclase activity in crude renal membrane preparations, compared with control rats. Despite the reduction of PTH-R mRNA and PTH-sensitive adenylyl cyclase in the kidney, CRF rats with intact parathyroid glands had lower urinary calcium excretion and higher phosphate excretion than CRF-TPTX rats, suggesting that PTH was still capable of controlling mineral ion metabolism through the remaining PTH-R in the residual nephrons. In conclusion, our data demonstrate that neither an increase in plasma PTH and phosphate nor a decrease in plasma calcium are important in renal PTH-R down-regulation during chronic renal failure. It is also unlikely that an increase in the locally-produced renal PTHrP could down-regulate its own receptor.