Positive and negative regulations of the renal 25-hydroxyvitamin D-3 1 alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1 alpha,25(OH)(2)D-3 in intact animals

Reflecting the prime role of 1 alpha,25(OH)(2)D-3 in calcium homeostasis, t he activity of 25-hydroxyvitamin D-3 1 alpha-hydroxylase, a key enzyme for 1 alpha,25(OH)(2)D-3 biosynthesis, is tightly regulated by 1 alpha,25(OH)(2 )D-3, PTH and calcitonin. Its significant activity is found in kidney, thou gh the enzymatic activity is also reported in extra-renal tissues. In the p resent study. we found that the 1 alpha-hydroxylase gene abundantly express es in kidney, and at low levels in other tissues and in some cell lines. Po sitive and negative regulations of 1 alpha-hydroxylase gene by PTH, calcito nin, or 1 alpha,25(OH)(2)D-3 were observed at transcriptional levels in kid neys of animals and in a mouse proximal tubule cell line. Moreover, the pro tein kinase A inhibitor abrogated the PTH-mediated positive regulation. In mice lacking the vitamin D receptor, the 1 alpha-hydroxylase gene expressio n was overinduced, and the inducible effect of either PTH or calcitonin, bu t not the repression by 1 alpha,25(OH)(2)D-3, was evident. Thus, vitamin D receptor is essential for the negative regulation by 1 alpha,25(OH)(2)D-3. Moreover, we demonstrate that renal 1 alpha-hydroxylase gene expression in chronic renal failure model rats was decreased and the positive effect by P TH and calcitonin was diminished. The present study demonstrates that PTH a nd calcitonin positively regulate renal 1 alpha-hydroxylase gene expression via PKA-dependent and independent pathway, respectively, and that 1 alpha, 25(OH)(2)D-3 negatively regulates it mediated by vitamin D receptor. Furthe rmore, in a moderate state of chronic renal failure, renal cells expressing the 1 alpha-hydroxylase gene appear to have diminished potential in respon se to PTH and calcitonin.