Background: Recent evidence points to a relationship between the down-regulation of the calcium-sensing receptor (CaR) and parathyroid cell hyperplasia that is associated with chronic renal failure. It is not known, however, if down-regulation of the CaR precedes, and perhaps initiates, parathyroid cell proliferation, or if a decrease in the expression of the CaR occurs subsequently to hyperplasia or the conditions promoting it. The current study examined the temporal relationship of these two events.
Methods: Rats were made uremic by subtotal nephrectomy and were (1) placed immediately on a high phosphate (HP) diet that promotes parathyroid gland hyperplasia, or (2) maintained on a low phosphate (LP) diet that inhibits development of secondary hyperparathyroidism before being switched to the HP diet. Serum chemistries and parathyroid gland (PTG) weights were examined; CaR content and parathyroid cell proliferation (PCNA/Ki-67) were analyzed by immunohistochemistry.
Results: When rats were nephrectomized and placed immediately on a HP diet, parathyroid cell proliferation was significantly increased by day 2 and continued to increase at day 4. CaR content was unchanged at 1 and 2 days post-nephrectomy, but fell by day 4. When nephrectomized rats were maintained for 1 week on a LP diet, then switched to a HP diet, an increase in parathyroid cell proliferation was again seen at day 2; down-regulation of the CaR did not occur until after 7 days of uremia and the HP diet.
Conclusion: These data indicate that parathyroid cell hyperplasia precedes down-regulation of CaR expression in the uremic rat model.