In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin d levels.
In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin d levels.
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DOI：
10.1161/circgenetics.108.847814
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Razzaque MS
中科院分区：
文献类型：
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作者：
Ohnishi M;Nakatani T;Lanske B;Razzaque MS
Klotho基因敲除小鼠（klotho-/-）的钠/磷酸盐共转运蛋白（NaPi 2a）的肾脏表达增加，与重度高磷酸盐血症相关。klotho-/-小鼠的这种血清生化变化导致广泛的软组织异常和血管钙化。为了确定klotho-/-小鼠中NaPi 2a蛋白的肾表达增加以及伴随的高磷酸盐血症和血管钙化的意义，我们产生了klotho和NaPi 2a双敲除（klotho-/-/NaPi 2a-/-）小鼠。来自klotho-/-小鼠的NaPi 2a活性的遗传失活将严重高磷酸盐血症逆转为轻度低磷酸盐血症或正常磷酸盐血症。重要的是，尽管klotho-/-/NaPi 2a-/-小鼠的血清钙和1，25-二羟基维生素D水平显著较高，但血管和软组织钙化减少。广泛的软组织异常和心血管钙化一致注意到在klotho-/-小鼠6周龄;然而，这些血管和软组织异常，甚至在12周龄的双基因敲除小鼠中不存在。Klotho-/-/NaPi 2a-/-小鼠也恢复了体重，并且没有出现在Klotho-/-单敲除小鼠中经常观察到的全身性组织萎缩。我们的体内遗传操作研究为增加NaPi 2a活性在调节klotho-/-小鼠中异常矿物质离子代谢和软组织异常中的病理作用提供了令人信服的证据。值得注意的是，我们的研究结果表明，血清磷酸盐水平是体内钙化的重要决定因素，降低血清磷酸盐水平可以减少或消除软组织和血管钙化，即使在极高的血清钙和1，25-二羟维生素D水平的存在下。这些体内观察结果对伴有心血管钙化的慢性肾脏病患者具有重要的临床意义和治疗意义。
Klotho knockout mice (klotho-/-) have increased renal expression of sodium/phosphate co-transporters (NaPi2a), associated with severe hyperphosphatemia. Such serum biochemical changes in klotho-/-mice lead to extensive soft tissue anomalies and vascular calcification. To determine the significance of increased renal expression of the NaPi2a protein and concomitant hyperphosphatemia and vascular calcification in klotho-/-mice, we generated klotho and NaPi2a double knockout (klotho-/-/NaPi2a-/-) mice. Genetic inactivation of NaPi2a activity from klotho-/-mice reversed the severe hyperphosphatemia to mild hypophosphatemia or normophosphatemia. Importantly, despite significantly higher serum calcium and 1,25-dihydroxyvitamin D levels in klotho-/-/NaPi2a-/- mice, the vascular and soft tissue calcifications were reduced,. Extensive soft tissue anomalies and cardiovascular calcification were consistently noted in klotho-/-mice by 6 weeks of age; however, these vascular and soft tissue abnormalities were absent even in 12-week-old double knockout mice. Klotho-/-/NaPi2a-/- mice also regained body weight and did not develop the generalized tissue atrophy often noted in klotho-/-single knockout mice. Our in vivo genetic manipulation studies have provided compelling evidence for a pathologic role of increased NaPi2a activities in regulating abnormal mineral ion metabolism and soft tissue anomalies in klotho-/- mice. Notably, our results suggest that serum phosphate levels are the important in vivo determinant of calcification, and that lowering serum phosphate levels can reduce or eliminate soft tissue and vascular calcification, even in presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels. These in vivo observations have significant clinical importance and therapeutic implications for chronic kidney disease patients with cardiovascular calcification.