Tenenhouse H S, Martel J, Gauthier C, Zhang M Y, Portale A A
Department of Pediatrics, McGill University-Montreal Children's Hospital Research Institute, Montréal, Québec, Canada H3H 1P3.
Endocrinology. 2001 Mar;142(3):1124-9. doi: 10.1210/endo.142.3.8029.
Several reports have suggested that the regulation of renal 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] synthesis by extracellular phosphate (Pi) is dependent on normal transepithelial Pi transport by the renal tubule. Mice homozygous for the disrupted Na/Pi cotransporter gene Npt2 (Npt2(-/-)) exhibit renal Pi wasting, an approximately 85% decrease in renal brush border membrane Na/Pi cotransport, hypophosphatemia, and an increase in serum 1,25-(OH)(2)D concentration. We undertook 1) to determine the mechanism for the increased circulating levels of 1,25-(OH)(2)D in Npt2(-/-) mice and 2) to establish whether renal 1alpha-hydroxylase was appropriately regulated by dietary Pi in the absence of Npt2 gene expression. On a control diet, the 2.5-fold increase in the serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice, relative to that in Npt2(+/+) littermates, is associated with a corresponding increase in renal mitochondrial 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity and messenger RNA (mRNA) abundance. A low Pi diet elicits an increase in serum 1,25-(OH)(2)D concentration, renal 1alpha-hydroxylase activity, and mRNA abundance in Npt2(+/+) and Npt2(-/-) mice to similar levels in both mouse strains. A high Pi diet has no effect on serum 1,25-(OH)(2)D concentration, renal 1 alpha-hydroxylase activity, or mRNA abundance in Npt2(+/+) mice, but normalizes these parameters in Npt2(-/-) mice. In addition, renal 24-hydroxylase mRNA abundance is significantly reduced in Npt2(-/-) mice compared with that in Npt2(+/+) mice under all dietary conditions. In summary, we demonstrate that 1) increased renal synthesis of 1,25-(OH)(2)D is responsible for the increased serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice; and 2) renal 1alpha-hydroxylase gene expression is appropriately regulated by dietary manipulation of serum Pi in both Npt2(+/+) and Npt2(-/-) mice. Thus, intact renal Na/Pi cotransport is not required for the regulation of renal 1alpha-hydroxylase by Pi.
几份报告表明，细胞外磷酸盐（Pi）对肾1,25 - 二羟维生素D [1,25 - (OH)(2)D]合成的调节依赖于肾小管正常的跨上皮Pi转运。Na/Pi共转运体基因Npt2纯合缺失的小鼠（Npt2(-/-)）表现出肾Pi流失、肾刷状缘膜Na/Pi共转运减少约85%、低磷血症以及血清1,25 - (OH)(2)D浓度升高。我们进行了以下两项研究：1）确定Npt2(-/-)小鼠中循环1,25 - (OH)(2)D水平升高的机制；2）确定在缺乏Npt2基因表达的情况下，膳食Pi是否能对肾1α - 羟化酶进行适当调节。在对照饮食条件下，与Npt2(+/+)同窝小鼠相比，Npt2(-/-)小鼠血清1,25 - (OH)(2)D浓度升高2.5倍，同时肾线粒体25 - 羟维生素D - 1α - 羟化酶（1α - 羟化酶）活性及信使核糖核酸（mRNA）丰度相应增加。低Pi饮食使Npt2(+/+)和Npt2(-/-)小鼠的血清1,25 - (OH)(2)D浓度、肾1α - 羟化酶活性及mRNA丰度升高至相似水平。高Pi饮食对Npt2(+/+)小鼠的血清1,25 - (OH)(2)D浓度、肾1α - 羟化酶活性或mRNA丰度无影响，但使Npt2(-/-)小鼠的这些参数恢复正常。此外，在所有饮食条件下，与Npt2(+/+)小鼠相比，Npt2(-/-)小鼠肾24 - 羟化酶mRNA丰度显著降低。总之，我们证明：1）肾1,25 - (OH)(2)D合成增加是Npt2(-/-)小鼠血清1,25 - (OH)(2)D浓度升高的原因；2）在Npt2(+/+)和Npt2(-/-)小鼠中，膳食Pi对血清Pi的调节可适当调控肾1α - 羟化酶基因表达。因此，Pi对肾1α - 羟化酶的调节并不需要完整的肾Na/Pi共转运。
