Down-regulation of the PTH/PTHrP receptor in uremia

Abstract

A bstract:Resistance to the action of PTH has been well characterized in the setting of chronic renal failure. Most evidence points to post-receptor abnormalities in its pathogenesis. The recent cloning of the PTH/PTHrP receptor (PTH-R) has permitted us to examine whether in a 5/6 nephrectomy rat model (CRF) the expression of the PTH-R gene is modified. First, we have found that the renal PTH-R mRNA expression is markedly decreased in CRF compared to normal rats. Diminished PTH-R transcripts were associated with a lower PTH-induced cAMP production in renal membranes in CRF suggesting a decrease in the PTH-R number or post-receptot modifications. Second, thyroparathyroidectomized (TPTX) rats with normal renal function had no change in the renal PTH-R expression whereas TPTX-CRF rats still showed a decreased renal PTH-R mRNA expression suggesting that high plasma PTH levels were not etiologically important in the observed down-regulation. Despite the renal PTH-R down-regulation, CRF rats had a normal renal handling of calcium. They also had a higher phosphate excretion than control rats. TPTX-CRF rats showed a decrease in renal tubular calcium reabsorption and a phosphate retention when compared with CRF animals with intact parathyroid glands. This suggests that a few available PTH-R in the kidney allow PTH to exert, to a certain extent, its physiological role in this experimental model of uremia. In conclusion, these findings indicate a down-regulation of the renal PTH-R expression in CRF which appears to be independent of parathyroid gland function. The relevance of this phenomenon in the setting of the secondary hyperparathyroidism of uremia remains to be elucidated.The kidney plays a crucial role in maintaining mineral ion and bone homeostasis. The distal parts of the nephron, namely the thick ascending limb of Henle's loop, distal convoluted, and connecting tubules are the main regulatory sites for the final excretion of calcium, phosphate, and magnesium in the urine. These nephron segments have receptors for several calciotropic hormones such as parathyroid hormone

Development of renal bone disease

“…[56], which allowed the documentation of the decrease of this receptor's mRNA expression at several tissue levels [34,35,57,58]. [56], which allowed the documentation of the decrease of this receptor's mRNA expression at several tissue levels [34,35,57,58].…”

“…Other factors probably modulate this receptor's expression in uraemia, with calcitriol being currently one of the most studied candidates [57,58]. This decrease is not induced by the increased levels of PTH or phosphorus and is not influenced by thyroparathyroidectomy.…”

“…Peripheral resistance to PTH action, usually indicated as being part of the ROD setting, gained consistency after the cloning of the PTH/PTHrP receptor mRNA in 1992, by Segre et al . [56], which allowed the documentation of the decrease of this receptor's mRNA expression at several tissue levels [34,35,57,58].…”

“…This decrease is not induced by the increased levels of PTH or phosphorus and is not influenced by thyroparathyroidectomy. Other factors probably modulate this receptor's expression in uraemia, with calcitriol being currently one of the most studied candidates [57,58].…”

Recent progress in PTH/PTHrP research

“…Alkaline phosphatase and osteocalcin levels reflect bone formation better than carboxyterminal propeptide of type 1 procollagen. Ure~a [20] studied whether the resistance to PTH in the uremic state may be related to the down-regulation system of PTH receptor. There was a decrease of the steady state PTH receptor mRNA in the kidney of uremic rats and a diminished PTH sensitive adenylate cyclase activity.…”