Deficient acid handling with distal RTA in the NBCe2 knockout mouse.
Deficient acid handling with distal RTA in the NBCe2 knockout mouse.
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DOI：
10.1152/ajprenal.00163.2015
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Donghai Wen;Yang Yuan;Ryan J. Cornelius;Huaqing Li;Paige Warner;Bangchen Wang;Jun Wang‐France;T. Boettger;S. Sansom
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文献类型：
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作者：
Donghai Wen;Yang Yuan;Ryan J. Cornelius;Huaqing Li;Paige Warner;Bangchen Wang;Jun Wang‐France;T. Boettger;S. Sansom
在许多情况下，远端肾小管酸中毒（dRTA）的发病机制尚不清楚。在本研究中，我们报告了一种缺乏产电Na（+）-HCO 3（-）协同转运蛋白的小鼠模型[NBCe 2/Slc 4a 5; NBCe 2敲除（KO）小鼠]在口服酸攻击后发生dRTA。在野生型小鼠的连接小管（CNT）中鉴定了NBCe 2表达，并且其表达在酸加载后显著增加。NBCe 2 KO小鼠在标准小鼠饮食中没有dRTA。然而，在酸负荷后，NBCe 2 KO小鼠表现出dRTA的完整特征，其特征在于尿酸化不足、高尿酸性低钾血症代谢性酸中毒和高钙尿症。另外的实验表明，NBCe 2 KO小鼠在CNT中具有降低的管腔跨上皮电位，如通过显微穿刺所揭示的。进一步的免疫荧光和Western blot实验发现，NBCe 2 KO小鼠质膜H（+）-ATP酶B1的表达增加。这些结果表明，由于CNT中管腔跨上皮电位降低，酸负荷的NBCe 2 KO小鼠出现尿K（+）和Ca（2+）消耗增加。NBCe 2 KO小鼠通过增加质膜中的H（+）-ATP酶来补偿以维持全身pH。因此，NBCe 2的缺陷可引起dRTA，并且NBCe 2在调节尿酸化和远端肾单位中K（+）和Ca（2+）的转运中具有重要作用。
In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. In the present study, we report that a mouse model lacking the electrogenic Na(+)-HCO3 (-) cotransporter [NBCe2/Slc4a5; NBCe2 knockout (KO) mice] developed dRTA after an oral acid challenge. NBCe2 expression was identified in the connecting tubule (CNT) of wild-type mice, and its expression was significantly increased after acid loading. NBCe2 KO mice did not have dRTA when on a standard mouse diet. However, after acid loading, NBCe2 KO mice exhibited complete features of dRTA, characterized by insufficient urinary acidification, hyperchloremic hypokalemic metabolic acidosis, and hypercalciuria. Additional experiments showed that NBCe2 KO mice had decreased luminal transepithelial potential in the CNT, as revealed by micropuncture. Further immunofluorescence and Western blot experiments found that NBCe2 KO mice had increased expression of H(+)-ATPase B1 in the plasma membrane. These results showed that NBCe2 KO mice with acid loading developed increased urinary K(+) and Ca(2+) wasting due to decreased luminal transepithelial potential in the CNT. NBCe2 KO mice compensated to maintain systemic pH by increasing H(+)-ATPase in the plasma membrane. Therefore, defects in NBCe2 can cause dRTA, and NBCe2 has an important role to regulate urinary acidification and the transport of K(+) and Ca(2+) in the distal nephron.