Dieter Michael, Palmada Monica, Rajamanickam Jeyaganesh, Aydin Atakan, Busjahn Andreas, Boehmer Christoph, Luft Friedrich C, Lang Florian
Department of Physiology I, University of Tübingen, Germany.
Obes Res. 2004 May;12(5):862-70. doi: 10.1038/oby.2004.104.
Serum- and glucocorticoid-inducible kinase 1 (SGK1) inhibits the ubiquitin ligase neuronal cell expressed developmentally downregulated 4-2 (Nedd4-2), which retards the retrieval of the epithelial Na+ channel ENaC. Accordingly, SGK1 enhances ENaC abundance in the cell membrane. The significance of this effect is shown by an association of an E8CC/CT;I6CC polymorphism in the SGK1 gene with increased blood pressure. However, strong expression of SGK1 in enterocytes not expressing ENaC points to further functions of SGK1. This study was performed to test for regulation of Na+-coupled glucose transporter 1 (SGLT1) by Nedd4-2, SGK1, and/or the related kinases SGK3 and PKB. Additional studies searched for an association of the SGK1 gene with BMI.
mRNA encoding SGLT1, wild-type Nedd4-2, inactive (C938S)Nedd4-2, wild type SGK1, constitutively active (S422D)SGK1 or inactive (K127N)SGK1, wild-type SGK3, and constitutively active (T308DS473D)PKB or inactive (T308AS473A)PKB were injected into Xenopus oocytes, and glucose transport was quantified from glucose-induced current (I(glc)). BMI was determined in individuals with or without the E8CC/CT;I6CC polymorphism.
I(glc) was significantly decreased by coexpression of Nedd4-2 but not of (C938S)Nedd4-2. Coexpression of SGK1, (S422D)SGK1, SGK3, or (T308DS473D)PKB, but not of (K127N)SGK1 or (T308AS473A)PKB, enhanced I(glc) and reversed the effect of Nedd4-2. SGK1 and SGK3 phosphorylated Nedd4-2. Deletion of the SGK/PKB phosphorylation sites in Nedd4-2 blunted the kinase effects. BMI was significantly (p < 0.008) greater in individuals with the E8CC/CT;I6CC polymorphism than in individuals without.
Overactivity of SGK1 may lead not only to excessive ENaC activity and hypertension but also to enhanced SGLT1 activity and obesity.
血清和糖皮质激素诱导激酶1（SGK1）可抑制泛素连接酶神经元细胞发育下调表达4-2（Nedd4-2），后者会延缓上皮钠通道ENaC的回收。因此，SGK1可提高细胞膜中ENaC的丰度。SGK1基因中的E8CC/CT;I6CC多态性与血压升高相关，这表明了这种作用的重要性。然而，SGK1在不表达ENaC的肠上皮细胞中强烈表达，这表明SGK1还有其他功能。本研究旨在检测Nedd4-2、SGK1和/或相关激酶SGK3及蛋白激酶B（PKB）对钠偶联葡萄糖转运体1（SGLT1）的调节作用。另外的研究则探寻SGK1基因与体重指数（BMI）之间的关联。
将编码SGLT1、野生型Nedd4-2、无活性（C938S）Nedd4-2、野生型SGK1、组成型活性（S422D）SGK1或无活性（K127N）SGK1、野生型SGK3以及组成型活性（T308DS473D）PKB或无活性（T308AS473A）PKB的mRNA注射到非洲爪蟾卵母细胞中，并根据葡萄糖诱导电流（I(glc)）对葡萄糖转运进行定量分析。对有或无E8CC/CT;I6CC多态性的个体测定BMI。
共表达Nedd4-2可使I(glc)显著降低，但共表达（C938S）Nedd4-2则不会。共表达SGK1、（S422D）SGK1、SGK3或（T308DS473D）PKB可增强I(glc)，并逆转Nedd�-2的作用，但共表达（K127N）SGK1或（T308AS473A）PKB则无此作用。SGK1和SGK3可使Nedd4-2磷酸化。缺失Nedd4-2中的SGK/PKB磷酸化位点会减弱激酶的作用。具有E8CC/CT;I6CC多态性的个体的BMI显著（p < 0.008）高于无此多态性的个体。
SGK1活性过高不仅可能导致ENaC活性过高和高血压，还可能导致SGLT1活性增强和肥胖。
