Role of vitamin D and parathyroid hormone on vitamin D metabolism in the kidney.

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It is well established that vitamin D_3 is first metabolized in the liver to 25-hydroxyvitamin D_3 and then in the kidney to 1alpha, 25-dihydroxyvitamin D_3.1alpha, 25-Dihydroxyvitamin D_3 synthesized by 25-hydroxyvitamin D_3-1alpha-hydroxylase is biologically the most active metabolite of the vitamin D, and vitamin D receptors mediate its effects by controlling transcription of vitamin D-responsive genes. 24, 25-Dihydroxyvitamin D_3 synthesized by 25-hydroxyvitamin D_3-24-hydroxylase is thought to be an inactive metabolite. The vitamin D endocrine system is regulated reciprocally by renal 25-hydroxyvitamin D_3-1alpha-and 24-hydroxylases. Previously, we reported that renal proximal convoluted tubules, the major site of 1alpha, 25-dihydroxyvitamin D_3 production, have vitamin D receptors. In the presence of vitamin D receptors, renal proximal convoluted tubules cannot maintain the state of enhanced production of 1alpha, 25-dihydroxyvitamin D_3. To clarify this discrepancy, we proposed a … More working hypothesis for the reciprocal control of renal 25-hydroxyvitamin D_3-1alpha-and 24-hydroxylase activities. In the rat models of enhanced renal production of 1alpha, 25-dihydroxyvitamin D_3, expression of vitamin D receptors and 25-hydroxyvitamin D_3-24-hydroxylase mRNAs was strikingly suppressed in renal proximal convoluted tubules, but not in the cortical collecting ducts. In vitamin D deficient rats with up-regulated renal 25-hydroxyvitamin D_3-1alpha-hydroxylase activity, expression of vitamin D receptor mRNA in renal proximal convoluted tubules was also down-regulated, indicating that the down-regulation of vitamin D receptor mRNA is not the result of the enhanced production of 1alpha, 25-dihydroxyvitamin D_3. In Japanese quail models with up-regulated renal 25-hydroxyvitamin D_3-1alpha-hydroxylase activity by sex steroids, expression of vitamin D receptor mRNA was also down-regulated in the kidney, but not in the duodenum. These results suggest that the down-regulation of vitamin D receptors plays a critical role in the production of 1alpha, 25-dihydroxyvitaminD_3 in renal proximal convoluted tubules. Less