Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification
Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification
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DOI：
10.1038/ki.2008.26
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发表时间：
2008-05-01
影响因子：
19.6
通讯作者：
O'Neill, W. C.
中科院分区：
文献类型：
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作者：
Lomashvili, K. A.;Garg, P.;O'Neill, W. C.
焦磷酸盐是一种有效的内侧血管钙化抑制剂，其水平由组织非特异性碱性磷酸酶(TNAP)的水解酶控制。我们试图确定增加的TNAP活性是否可以解释肾功能衰竭中出现的焦磷酸缺乏症和血管钙化。在喂饲腺嘌呤或5/6肾切除的尿毒症大鼠的完整主动脉和主动脉匀浆中，TNAP活性增加了两倍。免疫印迹显示蛋白质丰度增加，但定量聚合酶链式反应评估没有增加TNAP基因的表达。非特异性碱性磷酸酶抑制剂左旋咪唑可抑制大鼠主动脉环对焦磷酸盐的降解约一半，而缺乏TNAP的小鼠则可减少约一半。尿毒症大鼠主动脉环的水解度增加，左旋咪唑可抑制这一增加。正常大鼠的主动脉环与尿毒症大鼠血浆孵育后，TNAP活性和焦磷酸水解率也升高。这些结果提示，循环因子通过调节TNAP活性导致焦磷酸盐缺乏症，肾功能衰竭的血管钙化可能是该因子的作用所致。如果被未来的研究证实，这一机制将确定碱性磷酸酶为潜在的治疗靶点。
Pyrophosphate is a potent inhibitor of medial vascular calcification where its level is controlled by hydrolysis via a tissue-nonspecific alkaline phosphatase ( TNAP). We sought to determine if increased TNAP activity could explain the pyrophosphate deficiency and vascular calcification seen in renal failure. TNAP activity increased twofold in intact aortas and in aortic homogenates from rats made uremic by feeding adenine or by 5/6 nephrectomy. Immunoblotting showed an increase in protein abundance but there was no increase in TNAP mRNA assessed by quantitative polymerase chain reaction. Hydrolysis of pyrophosphate by rat aortic rings was inhibited about half by the nonspecific alkaline phosphatase inhibitor levamisole and was reduced about half in aortas from mice lacking TNAP. Hydrolysis was increased in aortic rings from uremic rats and all of this increase was inhibited by levamisole. An increase in TNAP activity and pyrophosphate hydrolysis also occurred when aortic rings from normal rats were incubated with uremic rat plasma. These results suggest that a circulating factor causes pyrophosphate deficiency by regulating TNAP activity and that vascular calcification in renal failure may result from the action of this factor. If proven by future studies, this mechanism will identify alkaline phosphatase as a potential therapeutic target.