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 potential ly implicated in this downregulation, to date only PTH has been demons trated to modulate PTH-R expression. Here, we examined the effect of t hyroparathyroidectomy (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 mea n(+/- 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 an d 511 +/- 156 in control and TPTX rats, respectively. Plasma phosphoru s, calcitriol, and ionized calcium were significantly lower in CRF and CRF+TPTX than in control animals. Plasma ionized calcium and calcitri ol 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 decrease d 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 l evel 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 r atios 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 w ith control rats: 0.59 versus 0.78, respectively. No change was observ ed in the renal PTH-R mRNA level in TPTX animals. There was also no ch ange in the PTH-R mRNA expression in the liver of uremic rats. The exp ression of the PTHrP mRNA was comparable in the kidney of control and CRF animals. CRF and CRF+TPTX rats showed a similarly reduced PTH-sens itive adenylyl cyclase activity in crude renal membrane preparations, compared with control rats. Despite the reduction of PTH-R mRNA and PT H-sensitive adenylyl cyclase in the kidney, CRF rats with intact parat hyroid glands had lower urinary calcium excretion and higher phosphate excretion than CRF-TPTX rats, suggesting that PTH was still capable o f controlling mineral ion metabolism through the remaining PTH-R in th e residual nephrons. In conclusion, our data demonstrate that neither an increase in plasma PTH and phosphate nor a decrease in plasma calci um are important in renal PTH-R down-regulation during chronic renal f ailure. It is also unlikely that an increase in the locally-produced r enal PTHrP could down-regulate its own receptor.