| Co-Investigator(Kenkyū-buntansha) |
KATAGIRI Takenobu Showa University, School of Dentistry, Assistant, 歯学部, 助手 (80245802)
MIYAURA Chisato Showa University, School of Dentistry, Lecturer, 歯学部, 講師 (20138382)
SUDA Tatsuo Showa University, School of Dentistry, Professor, 歯学部, 教授 (90014034)
宇田川 信之 昭和大学, 歯学部, 助手 (70245801)
瀧戸 次郎 昭和大学, 歯学部, 助手 (00197237)
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| Budget Amount *help |
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1995: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1994: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Research Abstract |
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
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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
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