Decreased Expression of Calcium Receptor in Parathyroid Tissue in Patients with Hyperparathyroidism Secondary to Chronic Renal Failure

Abstract

The response of parathyroid cells to serum calcium is regulated by a calcium-sensing receptor protein (CaR). In patients with chronic renal failure, hypocalcemia contributes to the parathyroid hyperplasia and increased parathyroid hormone secretion characteristic of secondary hyperparathyroidism (sHPT). However, patients with uremia also display reduced sensitivity to extracellular calcium; this seems to be owing to an alteration of the receptor mechanism. This study examined calcium receptor expression in the parathyroid tissue of patients with sHPT, using immunohistochemical techniques and comparison with normal tissue and parathyroid glands of patients with primary hyperparathyroidism. In all the glands studied, immunostaining was more intense in chief cells than in oxyphilic, transitional, and clear cells. The parathyroid glands of patients with sHPT displayed significantly reduced expression of CaR with respect to morphologically normal ones; a very similar reduction is reported in adenomas. Furthermore, in glands displaying multinodular hyperplasia, expression was less marked in nodule-forming cells than in internodular areas. The decreased expression of calcium receptors in the parathyroid tissue of uremic patients was thought to be owing to the different cell populations present; these parathyroid glands contained predominantly transitional, oxyphilic, and clear cells, which normally express fewer receptors than chief cells, which are more abundant in normal glands.

Calcium-sensing receptor in cancer: good cop or bad cop?

“…Expression of CaR mRNA produced by one of the two promoters of CaR gene was found to be specifically reduced in parathyroid adenomas. A lower expression of CaR mRNA and CaR protein has also been reported in parathyroid adenomas and hyperplastic glands from patients with uremic hyperparathyroidism [26,27].…”

Magnesium Depletion and Parathyroid Function

“…5 Vitamin D response elements have been identified at two promoter regions upstream from the transcription start site of the CaSR gene. 51 In chronic kidney disease, it is postulated that the parathyroid CaSR is reduced as a result of low serum levels of 1,25-dihydroxyvitamin D. 52,53 To follow this logic, Mg depletion would lead to low 1,25-dihydroxyvitamin D levels in serum that would be reflected in low parathyroid content of 1,25-dihydroxyvitamin D and hence decreased CaSR transcription. In theory, this is the opposite of what would be expected from Mg depletion, i.e., an up-regulation of the parathyroid CaSR.…”

The Parathyroids in Renal Disease

“…48 Expression of the CaSR is reduced by 30-70% as judged by immunohistochemical methods in hyperplastic parathyroid tissue obtained from human subjects with renal failure. 26,49 CaSR gene transcription is regulated by vitamin D through two distinct vitamin D response elements in the gene's promoter region. 50 Thus, alterations in vitamin D metabolism in renal failure could account for changes in calcium sensing by the parathyroid glands and vitamin D may act upstream of the CaSR in preventing parathyroid cell hyperplasia.…”