Schulz-Baldes A, Berger S, Grahammer F, Warth R, Goldschmidt I, Peters J, Schütz G, Greger R, Bleich M
Physiologisches Institut, Albert-Ludwigs Universität, 79104 Freiburg, Germany.
Pflugers Arch. 2001 Nov;443(2):297-305. doi: 10.1007/s004240100694.
Epithelial Na+ channel (ENaC) activity in kidney and colon is stimulated by aldosterone acting on the mineralocorticoid receptor (MR). MR and the glucocorticoid receptor (GR) show high homology in their DNA-binding domain and have similar affinities to mineralo- and glucocorticoids. We therefore asked whether the glucocorticoid-mediated activation of ENaC is restricted to the presence of MR and used the MR knockout mouse model to address this question. Due to their MR deficiency and the consecutive reduction of ENaC activity these mice die as neonates, and even after appropriate substitution therapy adult MR knockout mice suffer from high Na+ loss and hyperkalemia. In the present study, glucocorticoid treatment restored plasma K+ and almost normalized the fractional excretions of Na+ (FENa+) and K+ (FEK+) in adult salt-substituted MR knockout mice, while the effect of amiloride on FENa+ and FEK+ was augmented in these animals. In order to estimate ENaC activity, measurements of transepithelial equivalent short-circuit current (Isc) were performed. Glucocorticoids induced an amiloride-sensitive Na+ absorption in renal cortical collecting duct and distal colon of MR-/- of about 25% and 50% of the currents observed in glucocorticoid-treated wild-type mice, respectively. In the colon glucocorticoid treatment increased the mRNA abundance of all three ENaC subunits, in the kidney only alpha-ENaC was increased. The regulation of ENaC expression was the same in both genotypes and thus irrespective of the presence of MR. These data show that MR is no prerequisite for the activation of ENaC transcription and activity, and that the respective mechanisms can be stimulated via GR.
醛固酮作用于盐皮质激素受体（MR）可刺激肾脏和结肠中的上皮钠通道（ENaC）活性。MR与糖皮质激素受体（GR）在其DNA结合结构域中显示出高度同源性，并且对盐皮质激素和糖皮质激素具有相似的亲和力。因此，我们询问糖皮质激素介导的ENaC激活是否仅限于MR的存在，并使用MR基因敲除小鼠模型来解决这个问题。由于这些小鼠存在MR缺陷且ENaC活性持续降低，它们在新生儿期就会死亡，即使经过适当的替代治疗，成年MR基因敲除小鼠仍会出现高钠流失和高钾血症。在本研究中，糖皮质激素治疗可恢复成年盐替代MR基因敲除小鼠的血浆钾水平，并使钠（FENa +）和钾（FEK +）的分数排泄几乎正常化，而阿米洛利对FENa +和FEK +的作用在这些动物中增强。为了估计ENaC活性，进行了跨上皮等效短路电流（Isc）的测量。糖皮质激素在MR-/-的肾皮质集合管和远端结肠中诱导了阿米洛利敏感的钠吸收，分别约为糖皮质激素处理的野生型小鼠中观察到电流的25％和50％。在结肠中，糖皮质激素治疗增加了所有三个ENaC亚基的mRNA丰度，在肾脏中仅α-ENaC增加。两种基因型中ENaC表达的调节是相同的，因此与MR的存在无关。这些数据表明，MR不是激活ENaC转录和活性的先决条件，并且各自的机制可以通过GR刺激。
