Carpenter T O, Shiratori T
Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut 06510.
Am J Physiol. 1990 Dec;259(6 Pt 1):E814-21. doi: 10.1152/ajpendo.1990.259.6.E814.
The Hyp mouse is a homologue of the X chromosome-linked human disease, familial hypophosphatemic rickets (FHR). In FHR, reduced renal tubular brush-border membrane transport of phosphate results in hypophosphatemia and rickets. Both humans with FHR and Hyp mice have abnormal regulation of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase), a mitochondrial enzyme found in proximal renal tubular cell epithelia, the apparent site of defective brush-border membrane phosphate transport. No common pathophysiology for these defects has been demonstrated. We hypothesized that phosphate transport may be present in renal mitochondria from Hyp mice and that its regulation may be deranged in parallel with the mitochondrial 1 alpha-hydroxylase. Using inhibitor-stop techniques described for measurement of phosphate transport in liver mitochondria, we examined mitochondria in normal and Hyp mouse kidney and found them to be comparable. We performed manipulations known to alter 1 alpha-hydroxylase differentially in normal and Hyp mice, i.e., phosphorus deprivation and phosphorus loading, and found no effect on mitochondrial phosphate transport. We also subjected Hyp and normal mice to calcium and vitamin D deprivation; this maneuver resulted in no significant changes in mitochondrial phosphate transport in Hyp or normal mice but confirmed the earlier observation that 1 alpha-hydroxylase activity is stimulated to a greater degree in normal mice than Hyp mice after this diet. Furthermore, administration of 1,25-hydroxyvitamin D3 depresses 1 alpha-hydroxylase activity in mitochondria from both normal and Hyp mice but has no effect on mitochondrial phosphate transport. We conclude that the mechanism of abnormal vitamin D metabolism in Hyp mice is not related to a primary defect in renal mitochondrial phosphate transport.
Hyp小鼠是与X染色体连锁的人类疾病——家族性低磷血症佝偻病（FHR）的同源物。在FHR中，肾小管刷状缘膜对磷酸盐的转运减少导致低磷血症和佝偻病。患有FHR的人类和Hyp小鼠均存在25-羟维生素D-1α-羟化酶（1α-羟化酶）调节异常，该酶是一种位于近端肾小管上皮细胞的线粒体酶，是刷状缘膜磷酸盐转运缺陷的明显部位。尚未证实这些缺陷存在共同的病理生理学机制。我们推测Hyp小鼠的肾线粒体中可能存在磷酸盐转运，并且其调节可能与线粒体1α-羟化酶同时紊乱。我们使用描述用于测量肝线粒体中磷酸盐转运的抑制剂阻断技术，检查了正常和Hyp小鼠肾脏中的线粒体，发现它们具有可比性。我们进行了已知会在正常和Hyp小鼠中差异改变1α-羟化酶的操作，即磷缺乏和磷负荷，发现对线粒体磷酸盐转运没有影响。我们还让Hyp小鼠和正常小鼠缺乏钙和维生素D；这一操作在Hyp小鼠或正常小鼠的线粒体磷酸盐转运中未导致显著变化，但证实了早期的观察结果，即在此饮食后，正常小鼠的1α-羟化酶活性比Hyp小鼠受到更大程度的刺激。此外，给予1,25-二羟维生素D3可降低正常和Hyp小鼠线粒体中的1α-羟化酶活性，但对线粒体磷酸盐转运没有影响。我们得出结论，Hyp小鼠维生素D代谢异常的机制与肾线粒体磷酸盐转运的原发性缺陷无关。
