Abnormal regulation of renal 25-hydroxyvitamin D-1α-hydroxylase activity in X-linked hypophosphatemia:: A translational or post-translational defect
Abnormal regulation of renal 25-hydroxyvitamin D-1α-hydroxylase activity in X-linked hypophosphatemia:: A translational or post-translational defect
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DOI：
10.1359/jbmr.2003.18.3.434
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发表时间：
2003-03-01
影响因子：
6.2
通讯作者：
Drezner, MK
中科院分区：
文献类型：
--
作者：
Fujiwara, I;Aravindan, R;Drezner, MK
Hyp小鼠表现出肾脏25（OH）D-1 α-羟化酶活性的代谢/激素调节异常。这是否是由于1 α-羟化酶基因CYP 27 B1的异常转录调节所致，目前尚不清楚。为了研究这种可能性，我们比较了磷酸盐和甲状旁腺激素对肾近曲小管的影响，以及甲状腺降钙素对正常和hypp小鼠近直小管酶活性和mRNA表达的影响。我们通过测量1，25（OH）（2）D的产生和核糖核酸酶保护的mRNA来测定25（OH）D-1 α-羟化酶活性。与正常小鼠相比，磷酸盐耗尽小鼠的25（OH）D-1 α-羟化酶活性增加了3倍，而hyp小鼠的酶功能没有增强。磷酸盐耗尽的小鼠同时表现出2倍的mRNA转录增加，相反，尽管未能改变酶的活性，hypmice表现出类似的增量mRNA转录。甲状旁腺激素刺激正常小鼠的25（OH）D-1 α-羟化酶活性增加10倍，而只引起hypmouse酶功能增加2倍。尽管mRNA转录物增加到相当的水平（22.2 +/- 3.5-对19.9 +/- 1.8-倍），但仍发生了这种差异。磷酸盐和甲状旁腺素介导的转录活性和蛋白质功能之间的解离并不普遍。因此，正常和hypp小鼠的甲状腺降钙素刺激导致mRNA转录和酶活性的可比增强。这些观察结果表明，维生素D代谢的异常调节hypmice发生在近曲小管和结果，而不是从异常的转录调控，但从翻译或翻译后活性的缺陷。
The hyp mouse exhibits abnormal metabolic/hormonal regulation of renal 25(OH)D-1alpha-hydroxylase activity. Whether this results from aberrant transcriptional regulation of the 1alpha-hydroxylase gene, CYP27B1, remains unknown. To investigate this possibility, we compared phosphate and parathyroid hormone effects on renal proximal convoluted tubule and thyrocalcitonin effects on proximal straight tubule enzyme activity and mRNA expression in normal and hyp mice. We assayed 25(OH)D-1alpha-hydroxylase activity by measuring 1,25(OH)(2)D production and mRNA by ribonuclease protection. Phosphate-depleted mice exhibited a 3-fold increment of 25(OH)D-1alpha-hydroxylase activity compared with normals, whereas hyp mice displayed no enhanced enzyme function. Phosphate-depleted mice concurrently displayed a 2-fold increase in mRNA transcripts; in contrast, despite failure to alter enzyme activity, hyp mice exhibited a similar increment in mRNA transcripts. Parathyroid hormone stimulation of normal mice increased 25(OH)D-1alpha-hydroxylase activity 10-fold,while eliciting only a 2-fold increment in hyp mouse enzyme function. This disparity occurred despite increments of mRNA transcripts to comparable levels (22.2 +/- 3.5- vs. 19.9 +/- 1.8-fold). The dissociation between phosphate- and parathyroid hormone-mediated transcriptional activity and protein function was not universal. Thus, thyrocalcitonin stimulation of normal and hyp mice resulted in comparable enhancement of mRNA transcripts and enzyme activity. These observations indicate that abnormal regulation of vitamin D metabolism in hyp mice occurs in the proximal convoluted tubule and results, not from aberrant transcriptional regulation, but from a defect in translational or post-translational activity.