Alex J. Brown, Ph.D.

DEPARTMENT OF Int Med - Renal
Keywords: vitamin D, calcium receptor, parathyroid, calcium, renal transplantation

The parathyroid glands express a cell surface calcium-sensing receptor (CaR) that monitors extracellular calcium levels and signals the glands to secrete the proper amount of the calciotropic hormone, parathyroid hormone (PTH), to maintain normal blood calcium. This control of calcium homeostasis is abnormal in hyperplastic parathyroid glands of patients with primary hyperparathyroidism and secondary hyperparathyroidism due to chronic renal disease. Recent findings indicate that the CaR is down-regulated in hyperplastic tissues, but elucidation of the factors responsible is difficult to determine in patients. Using a rat model of renal failure that leads to secondary hyperparathyroidism, we have reproduced this down-regulation of the parathyroid gland CaR. Furthermore, we have found that dietary phosphate restriction, which prevents or arrests parathyroid hyperplasia, maintains or restores normal CaR expression in renal failure rats. Time-course studies indicate that the down-regulation occurs after the onset of parathyroid cell proliferation. We are currently examining the promoter region of the CaR gene to determine the molecular basis for the control of CaR expression.

Our laboratory also has been involved in the development of vitamin D analogs for the treatment of secondary hyperparathyroidism in renal failure patients. The analogs, like the natural vitamin D hormone calcitriol, decrease PTH secretion by suppressing PTH gene expression. However, the analogs have a lower tendency than calcitriol to produce hypercalcemia and therefore offer a safer alternative for treatment of patients. We are examining the mechanisms responsible for the lower calcemic responses to analogs in the intestine and bone.