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首页> 外文期刊>American Journal of Physiology >Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice
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Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice

机译：靶向缺失NCOA7基因导致小鼠中不完全的远端肾小管酸中毒

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We recently reported that nuclear receptor coactivator 7 (Ncoa7) is a vacuolar proton pumping ATPase (V-ATPase) interacting protein whose function has not been denned. Ncoa7 is highly expressed in the kidney and partially colocalizes with the V-ATPase in collecting duct intercalated cells (ICs). Here, we hypothesized that targeted deletion of the Ncoal gene could affect V-ATPase activity in ICs in vivo. We tested this by analyzing the acid-base status, major electrolytes, and kidney morphology of Ncoa7 knockout (KO) mice. We found that Ncoa7 KO mice, similar to Atp6vlbl KOs, did not develop severe distal renal tubular acidosis (dRTA), but they exhibited a persistently high urine pH and developed hypobicarbonatemia after acid loading with ammonium chloride. Conversely, they did not develop significant hyper-bicarbonatemia and alkalemia after alkali loading with sodium bicarbonate. We also found that ICs were larger and with more developed apical microvilli in Ncoal KO compared with wild-type mice, a phenolype previously associated with metabolic acidosis. At the molecular level, the abundance of several V-ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 was significantly reduced in medullary ICs of Ncoa7 KO mice, suggesting that Ncoa7 is important for maintaining high levels of these proteins in the kidney. We conclude that Ncoa7 is involved in IC function and urine acidification in mice in vivo, likely through modulating the abundance of V-ATPase and other key acid-base regulators in the renal medulla. Consequently, mutations in the NCOA7 gene may also be involved in dRTA pathogenesis in humans.
机译：我们最近报道，核受体共催胶剂7（NCOA7）是一种真空质子泵送ATP酶（V-ATP酶）相互作用蛋白，其功能尚未被欺骗。 NCOA7在肾脏中高度表达，并在收集导管插入细胞（IC）中与V-ATP酶部分结合。这里，我们假设靶向缺失的NCOAL基因可能影响体内IC中的V-ATP酶活性。我们通过分析NCOA7敲除（KO）小鼠的酸碱状态，主要电解质和肾脏形态来测试这一点。我们发现，类似于ATP6VLBL KOS的NCOA7 KO小鼠并未产生严重的远端肾小管酸中毒（DRTA），但它们在氯化铵酸载荷后表现出持续高尿液pH和开发的缺氧血症。相反，它们在碱性碳酸氢钠碱加载后，它们并未形成显着的超脂肪糖尿病和碱性血症。我们还发现，与野生型小鼠相比，NCOAL KO中的ICS越来越大，并且在NCOAL KO中，与野生型小鼠相比，一种先前与代谢酸中毒相关的酚型。在NCOA7KO小鼠的髓质IC中，在分子水平下，碳酸酐酶2和阴离子交换器1的丰度显着降低，表明NCOA7对于维持肾中的高水平这些蛋白质是重要的。我们得出结论，NCOA7参与体内小鼠的IC功能和尿酸酸化，可能通过调节肾髓质中的肾脏酶和其他重种酸碱稳压剂的丰度。因此，NCOA7基因中的突变也可以参与人体中的DRTA发病机制。

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