Association of the Serum and Glucocorticoid Regulated Kinase (sgk1) Gene with QT Interval

Abstract

The serum and glucocorticoid inducible kinase (SGK1) is well known to up-regulate the renal epithelial Na⁺ channel ENaC. Excessive SGK1 activity would be expected to cause renal Na⁺ retention and blood pressure increase. Certain polymorphisms of the SGK1 gene (E8CC/CT;I6CC) are indeed associated with moderately enhanced blood pressure. We have recently disclosed another function of SGK1, i.e. the stimulation of the slowly activating K⁺ channel KCNE1/KCNQ1. Among the functions of this channel is the repolarisation of cardiac myocytes. Accordingly, defective KCNE1 and/or KCNQ1 lead to long QT syndrome, a disorder causing fainting and sudden cardiac death. In the present study we demonstrate that coexpression of SGK1 in Xenopus oocytes increases KCNQ1/KCNE1 induced current without significantly altering voltage dependence, activation and deactivation kinetics. To test for the relevance of SGK1 in human cardiac repolarization, we analysed the ECG of monozygotic (MZ) (126 pairs) and dizygotic (DZ) (70 pairs) twin subjects and parents of DZ twins. The E8CC/CT;I6CC polymorphism was indeed significantly (p<0.025) associated with shortened age and gender corrected QT interval. No significant differences were observed in any other ECG parameter, including heart rate, P, PQ and QRS. We conclude that the regulation of KCNE1/KCNQ1 by SGK1 is similarly relevant for the repolarization of cardiac myocytes as for regulation of renal ENaC activity and blood pressure control.

The Serum- and Glucocorticoid-inducible Kinases SGK1 and SGK3 Regulate hERG Channel Expression via Ubiquitin Ligase Nedd4-2 and GTPase Rab11

“…For example, it has been reported that psychosocial stress plays a role in otherwise unexplained cardiac arrest (39). Furthermore, a gain-of-function SGK1 mutation has been reported in twins who displayed the shortened QT interval, which induces arrhythmias and sudden death (40,41).…”

Resistance of mice lacking the serum- and glucocorticoid-inducible kinase SGK1 against salt-sensitive hypertension induced by a high-fat diet

“…The increased body mass index may partially be due to enhanced stimulation of the intestinal glucose transporter SGLT1 (25), the accelerated cardiac repolarization being due to enhanced activation of the cardiac K ϩ channel KCNE1 (17,29). Thus altered regulation of carriers and channels by SGK1 could account for the coincidence of obesity, hypertension, and altered cardiac action potential (45).…”

SGK1-sensitive renal tubular glucose reabsorption in diabetes

“…Beyond its effect on nutrient transporters, SGK1 is a potent regulator of renal electrolyte transporters, such as the epithelial Na ϩ channel ENaC (2,17,23,26,27,32,57,73,81,84), the renal K ϩ channels ROMK (60,87,91) and KCNE1/KCNQ1 (22,30), the epithelial Ca 2ϩ channel TRPV5 (31, 58), the Na ϩ /H ϩ exchanger NHE3 (89,90), the Na ϩ -K ϩ -2Cl Ϫ cotransporter NKCC2, and the Na ϩ -K ϩ -ATPase (39,69,92). SGK1 contributes to the effect of aldosterone, IGF-1, and insulin on ENaC activity and thus renal salt reabsorption (7)(8)(9)(10)84).…”

“…SGK1 contributes to the effect of aldosterone, IGF-1, and insulin on ENaC activity and thus renal salt reabsorption (7)(8)(9)(10)84). A gene variant of the SGK1 gene is associated with increased blood pressure (21,22,80) and obesity (28). Therefore, SGK1 has been suggested as a candidate for the development of metabolic syndrome (46).…”