Prié Dominique, Beck Laurent, Urena Pablo, Friedlander Gérard
Inserm U 426 et Institut Fédératif de Recherche 02, Faculty of Medicine, Xavier Bichat, Paris, France.
Curr Opin Nephrol Hypertens. 2005 Jul;14(4):318-24. doi: 10.1097/01.mnh.0000172716.41853.1e.
We summarize the most recent findings on the proteins that interact with sodium/inorganic phosphate (Na/Pi) cotransporters, the factors that regulate Pi homeostasis and their role in pathology.
Studies in animal models and cell lines identified proteins mandatory to correct trafficking of the kidney-specific Na/Pi cotransporter NPT2a and its control by the parathyroid hormone. Expression of the intestinal cotransporter NPT2b is controlled by calcitriol, the ubiquitin ligase Nedd-4 and the serum glucocorticoid inducible kinase. Recent data confirm that fibroblast growth factor 23 plays a central role in the control of Pi homeostasis. Mice disrupted for or overexpressing this gene exhibit significant alteration of Pi transport and calcitriol metabolism. In humans, fibroblast growth factor 23 mutations are responsible for autosomal hypophosphataemic rickets or tumoral calcinosis. This gene also seems to be involved in hyperparathyroidism in patients with chronic kidney disease. Several new phosphaturic factors have been identified. Moderate increases in serum Pi concentration may have deleterious effects on lifespan in humans with chronic kidney disease. Disruption of the Klotho gene in mice is associated with hyperphosphataemia and decreased lifespan. Polymorphisms in this gene, in humans and in mice, influence vascular calcification and survival.
Pi homeostasis depends on the activity of Na/Pi cotransporters in intestine and kidney. Na/Pi transporter activity is regulated by cellular and endocrine factors, among which fibroblast growth factor 23 plays a central role. Adequate control of Pi homeostasis is crucial, as a moderate increase in serum Pi concentration and polymorphisms in genes involved in Pi metabolism may influence the aging process and lifespan.
我们总结了与钠/无机磷（Na/Pi）共转运蛋白相互作用的蛋白质、调节磷稳态的因素及其在病理学中的作用的最新研究结果。
在动物模型和细胞系中的研究确定了肾脏特异性Na/Pi共转运蛋白NPT2a正确转运及其受甲状旁腺激素调控所必需的蛋白质。肠道共转运蛋白NPT2b的表达受骨化三醇、泛素连接酶Nedd-4和血清糖皮质激素诱导激酶的控制。最近的数据证实，成纤维细胞生长因子23在磷稳态的控制中起核心作用。敲除或过表达该基因的小鼠表现出磷转运和骨化三醇代谢的显著改变。在人类中，成纤维细胞生长因子23突变导致常染色体低磷血症佝偻病或肿瘤性钙化。该基因似乎也与慢性肾脏病患者的甲状旁腺功能亢进有关。已鉴定出几种新的磷尿因子。血清磷浓度的适度升高可能对慢性肾脏病患者的寿命产生有害影响。小鼠中Klotho基因的破坏与高磷血症和寿命缩短有关。该基因在人类和小鼠中的多态性影响血管钙化和生存。
磷稳态取决于肠道和肾脏中Na/Pi共转运蛋白的活性。Na/Pi转运蛋白活性受细胞和内分泌因素调节，其中成纤维细胞生长因子23起核心作用。充分控制磷稳态至关重要，因为血清磷浓度的适度升高和参与磷代谢的基因多态性可能影响衰老过程和寿命。
