Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule
Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule
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DOI：
10.1074/jbc.273.44.29150
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发表时间：
1998-10-30
影响因子：
4.8
通讯作者：
Shull, GE
中科院分区：
文献类型：
--
作者：
Schultheis, PJ;Lorenz, JN;Shull, GE
编码远曲小管噻嗪敏感性Na+-Cl-协同转运蛋白（NCC）的基因突变导致Gitelman综合征，这是一种遗传性低钾血症，伴有低镁血症和低钙尿症。这些代谢异常继发于NaCl重吸收缺陷，但其潜在机制尚不清楚。为了更好地了解NCC在钠和液体容量稳态中的作用以及在Gitelman综合征的发病机制中的作用，我们使用基因靶向来制备NCC缺陷小鼠。Ncc突变（Ncc（-/-））小鼠看起来健康，并且在酸碱平衡、血浆电解质浓度、血清醛固酮水平和血压方面正常。Ncc（-/-）小鼠在喂食Na+耗竭饮食时保留Na+以及野生型小鼠;然而，在Na+耗竭2周后，Ncc（-/-）小鼠的平均动脉血压显著低于野生型小鼠。此外，Ncc（-/-）小鼠表现出肾脏中的肾素mRNA水平增加、低镁血症和低钙尿症以及远曲小管中的形态学变化。这些数据表明，小鼠中NCC活性的丧失仅引起钠和液体体积稳态的轻微扰动，但肾脏对Mg 2+和Ca 2+的处理发生改变，如在Gitelman综合征中观察到的。
Mutations in the gene encoding the thiazide-sensitive Na+-Cl- cotransporter (NCC) of the distal convoluted tubule cause Gitelman's syndrome, an inherited hypokalemic alkalosis with hypomagnesemia and hypocalciuria, These metabolic abnormalities are secondary to the deficit in NaCl reabsorption, but the underlying mechanisms are unclear. To gain a better understanding of the role of NCC in sodium and fluid volume homeostasis and in the pathogenesis of Gitelman's syndrome, we used gene targeting to prepare an NCC-deficient mouse. Null mutant (Ncc(-/-)) mice appear healthy and are normal with respect to acid-base balance, plasma electrolyte concentrations, serum aldosterone levels, and blood pressure. Ncc(-/-) mice retain Na+ as well as wild-type mice when fed a Na+-depleted diet; however, after 2 weeks of Na+ depletion the mean arterial blood pressure of Ncc(-/-) mice was significantly lower than that of wild-type mice. In addition, Ncc(-/-) mice exhibited increased renin mRNA levels in kidney, hypomagnesemia and hypocalciuria, and morphological changes in the distal convoluted tubule, These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg2+ and Ca2+ are altered, as observed in Gitelman's syndrome.