Parathyroidectomy does not prevent the renal PTH/PTHrP receptor down-regulation in uremic rats

Pablo Ureña, Michael Mannstadt, Milan Hruby, Aníbal Ferreira, François Schmitt, Caroline Silve, Raymond Ardaillou, Bernard Lacour, Abdul Badi Abou-Samra, Gino V. Segre, Tilman Drüeke

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62 Citations (Scopus)

Abstract

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 (μl/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 CRF+TPTX (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 CRF+TPTX rats was markedly decreased compared with that of control rats, the ratios of PTH-R mRNA/β-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 PTJHr-R 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.

Original languageEnglish
Pages (from-to)1797-1805
Number of pages9
JournalKidney International
Volume47
Issue number6
DOIs
Publication statusPublished - 1995

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