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Positive and Negative Regulations of the Renal 25-Hydroxyvitamin D3 1α-Hydroxylase Gene by Parathyroid Hormone, Calcitonin, and 1α,25(OH)2D3 in Intact Animals.

Reflecting the prime role of 1α,25(OH)2D3 in calcium homeostasis, the activity of 25-hydroxyvitamin D3 1α-hydroxylase, a key enzyme for 1α,25(OH)2D3 biosynthesis, is tightly regulated by 1α,25(OH)2D3, PTH and calcitonin. Its significant activity is found in kidney, though the enzymatic activity is also reported in extra-renal tissues. In the present study, we found that the 1α-hydroxylase gene abundantly expresses in kidney, and at low levels in other tissues and in some cell lines. Positive and negative regulations of 1α-hydroxylase gene by PTH, calcitonin, or 1α,25(OH)2D3 were observed at transcriptional levels in kidneys of animals and in a mouse proximal tubule cell line. Moreover, the protein kinase A inhibitor abrogated the PTH-mediated positive regulation. In mice lacking the vitamin D receptor, the 1α-hydroxylase gene expression was overinduced, and the inducible effect of either PTH or calcitonin, but not the repression by 1α,25(OH)2D3, was evident. Thus, vitamin D receptor is essential for the n...