The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion
The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion
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DOI：
10.1007/s00424-016-1798-5
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发表时间：
2016-05-01
影响因子：
4.5
通讯作者：
Loffing, Johannes
中科院分区：
文献类型：
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作者：
Czogalla, Jan;Vohra, Twinkle;Loffing, Johannes
醛固酮与盐皮质激素受体（MR）结合，通过上调上皮Na+通道（ENaC）和集合系统（CS）中的Na+-K+-ATP酶，也可能通过远曲小管（DCT）中的NaCl协同转运蛋白（NCC），增加肾脏Na+重吸收。然而，醛固酮是通过MR直接调节NCC还是通过全身改变间接调节NCC仍存在争议。我们使用了在类似于20%的肾小管细胞中缺失MR的小鼠（MR/X小鼠），其中MR阳性（MRwt）和MR阴性（MRko）细胞可以在相同的生理背景下并排研究。成年MR/X小鼠肾离子转运蛋白的mRNA和蛋白水平与对照小鼠相似。在MR/X小鼠中，MRwt和MRko细胞之间的NCC丰度和磷酸化没有差异，并且饮食Na+限制在两组细胞中上调NCC的程度相似。相比之下，CS中的MRko细胞在对照饮食和对饮食Na+限制的反应中都没有显示出任何可检测的α-ENaC丰度或ENaC的顶端靶向。此外，Na+-K+-ATP酶的表达在DCT的MRko细胞中不受影响，而在CS的MRko细胞中丢失。总之，MR对CS中的ENaC和Na+-K+-ATP酶的调节至关重要，但对DCT中的NCC和Na+-K+-ATP酶的调节不重要。
Aldosterone binds to the mineralocorticoid receptor (MR) and increases renal Na+ reabsorption via up-regulation of the epithelial Na+ channel (ENaC) and the Na+-K+-ATPase in the collecting system (CS) and possibly also via the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR or indirectly through systemic alterations remains controversial. We used mice with deletion of MR in similar to 20 % of renal tubule cells (MR/X mice), in which MR-positive (MRwt) and -negative (MRko) cells can be studied side-by-side in the same physiological context. Adult MR/X mice showed similar mRNA and protein levels of renal ion transport proteins to control mice. In MR/X mice, no differences in NCC abundance and phosphorylation was seen between MRwt and MRko cells and dietary Na+ restriction up-regulated NCC to similar extent in both groups of cells. In contrast, MRko cells in the CS did not show any detectable alpha-ENaC abundance or apical targeting of ENaC neither on control diet nor in response to dietary Na+ restriction. Furthermore, Na+-K+-ATPase expression was unaffected in MRko cells of the DCT, while it was lost in MRko cells of the CS. In conclusion, MR is crucial for ENaC and Na+-K+-ATPase regulation in the CS, but is dispensable for NCC and Na+-K+-ATPase regulation in the DCT.