The role of vitamin D in the pathogenesis: Role of calcium

Posted by James

Calcium is a key regulator factor in secondary HPT progression. Low serum calcium levels decrease the activation of the Calci­um-Sensing Receptor (CaSR), a plasma membrane G-protein coupled molecule that allows parathyroid cells to sense calcium in the extracellular fluid, thus greatly promoting PTH synthesis and secretion. In contrast, hypercalcemia activates the CaSR, rapidly suppressing secondary HPT. Recent evidence suggests that signaling through the CaSR plays an important role on parathyroid hyperplasia. Moreover, calcium-depend­ing signaling through the CaSR may prevent parathyroid hyper- plasia even in tissues that are not-responders to vitamin D. The extracellular calcium concentration may also regulate the level of PTH mRNA and parathyroid cell proliferation. Moreover, calcium regulates VDR mRNA and protein ex­pression in parathyroid cells independently of 1,25(OH)₂D. Clearly, serum calcium levels could also indirectly regulate PTH levels through a feedback of 1,25(OH)₂D on the parathy­roid glands.

Reduced expression of CaSR in hyperplastic parathyroid glands has been demonstrated in an animal model. Parathyroid hyperplasia appears 48 hours after 5/6 nephrecto- my in rats fed a high phosphate diet, while CaSR expression starts to decrease 48 hours later. Furthermore, in humans, CaSR content declines by about 60% in hyperplastic parathy­roid glands compared to normal controls. Further support for the pathophysiological relevance of changes in the expression of parathyroid p21, TGFa and EGFR in con­trolling proliferative activity came from studies, evaluating the expression of these three proteins after suppression of parathyroid cell growth by high-calcium intake or its further en­hancement by low dietary calcium. High dietary calcium con­trolled uremia-induced parathyroid hyperplasia, reducing both parathyroid gland size and the expression of two markers of mitotic activity, Ki67 and PCNA. Furthermore, high calcium diet increased parathyroid p21 levels and prevented the rise in parathyroid content of TGFa and EGFR induced by uremia. The mechanisms for high-calcium induction of p21 and prevention of the increase in TGFa and EGFR are un­known. Studies in vitamin D receptor-ablated mice showed the ability of a calcium-enriched diet to prevent the development of parathyroid hyperplasia in both hypocalcemic and normacalcemic states.

In relation to high-calcium control of TGFa/EGFR growth pro­moting signal, hypercalcemia and low plasma levels of TGFa were recently associated in cancer patients, suggesting the possibility of the systemic control of TGFa expression by calci­um. The existence of such an association in CRF patients could partially explain the suppression of parathyroid growth by hypercalcemia.

The changes in p21, TGFa and EGFR in the parathyroid glands of uremic rats fed a high Ca diet suggest that increases in serum calcium or in intracellular calcium, induced by vitamin D therapy, could enhance the effects of vitamin D itself in in­creasing p21 expression and reducing TGFa and EGFR con­tent. You can afford your pills. Buy cheap viagra online