Pendrin abundance, subcellular distribution, and function are unaffected by either αENaC gene ablation or by increasing ENaC channel activity.
Pendrin abundance, subcellular distribution, and function are unaffected by either αENaC gene ablation or by increasing ENaC channel activity.
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DOI：
10.1007/s00424-023-02797-w
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发表时间：
2023-05
影响因子：
4.5
通讯作者：
Wall, Susan M.
中科院分区：
文献类型：
--
作者：
Loffing, Johannes;Pech, Vladimir;Loffing-Cueni, Dominique;Abood, Delaney C.;Kim, Young Hee;Chen, Chao;Pham, Truyen D.;Verlander, Jill W.;Wall, Susan M.
插入细胞的Cl−/HCO 3 −交换器，pendrin，调节ENaC亚基的丰度和功能。然而，ENaC是否调节pendrin丰度和功能尚不清楚。由于在pendrin阳性的嵌入细胞中检测到αENaC mRNA，我们假设ENaC，或更具体地说αENaC亚基，调节嵌入细胞功能。因此，本研究的目的是确定αENaC是否在pendrin阳性嵌入细胞中以蛋白质水平表达，并确定αENaC基因消融或组成性上调ENaC活性是否改变pendrin丰度、亚细胞分布和/或功能。我们在小鼠和大鼠的pendrin阳性嵌入细胞中观察到弥漫性的细胞质αENaC标记，在pendrin阴性的A型嵌入细胞中的标记强度要低得多。然而，虽然CCD的主细胞和闰细胞内的αENaC基因切除减少了Cl−吸收，但它并没有改变醛固酮治疗小鼠中pendrin的丰度或亚细胞分布。进一步的实验使用Liddle综合征的小鼠模型来探索增加ENaC通道活性对pendrin丰度和功能的影响。Liddle的变体没有增加醛固酮治疗或NaCl限制小鼠的总或顶端质膜pendrin丰度。类似地，虽然Liddle突变增加了醛固酮处理小鼠CCD中的总Cl−吸收，但它并没有显著影响pendrin基因消融所见的Cl−吸收变化。我们得出结论，在大鼠和小鼠中，αENaC定位于pendrin阳性IC，其生理作用仍有待确定。虽然pendrin调节ENaC丰度、亚细胞分布和功能，但ENaC对pendrin没有类似的作用。
The intercalated cell Cl−/HCO3− exchanger, pendrin, modulates ENaC subunit abundance and function. Whether ENaC modulates pendrin abundance and function is however unknown. Because αENaC mRNA has been detected in pendrin-positive intercalated cells, we hypothesized that ENaC, or more specifically the αENaC subunit, modulates intercalated cell function. The purpose of this study was therefore to determine if αENaC is expressed at the protein level in pendrin-positive intercalated cells and to determine if αENaC gene ablation or constitutively upregulating ENaC activity changes pendrin abundance, subcellular distribution, and/or function. We observed diffuse, cytoplasmic αENaC label in pendrin-positive intercalated cells from both mice and rats, with much lower label intensity in pendrin-negative, type A intercalated cells. However, while αENaC gene ablation within principal and intercalated cells of the CCD reduced Cl− absorption, it did not change pendrin abundance or subcellular distribution in aldosterone-treated mice. Further experiments used a mouse model of Liddle’s syndrome to explore the effect of increasing ENaC channel activity on pendrin abundance and function. The Liddle’s variant did not increase either total or apical plasma membrane pendrin abundance in aldosterone-treated or in NaCl-restricted mice. Similarly, while the Liddle’s mutation increased total Cl− absorption in CCDs from aldosterone-treated mice, it did not significantly affect the change in Cl− absorption seen with pendrin gene ablation. We conclude that in rats and mice, αENaC localizes to pendrin-positive ICs where its physiological role remains to be determined. While pendrin modulates ENaC abundance, subcellular distribution, and function, ENaC does not have a similar effect on pendrin.
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DOI：
10.1073/pnas.1710964114
发表时间：
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影响因子：
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