Ackermann Teresa F, Boini Krishna M, Beier Norbert, Scholz Wolfgang, Fuchss Thomas, Lang Florian
Department of Physiology, University of Tübingen, Tübingen, Germany.
Cell Physiol Biochem. 2011;28(1):137-46. doi: 10.1159/000331722. Epub 2011 Aug 16.
The serum- and glucocorticoid-inducible kinase 1 (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase enhances renal tubular Na(+)-reabsorption and accounts for blood pressure increase following high salt diet in mice made hyperinsulinemic by dietary fructose or fat. The present study describes the in vitro and in vivo efficacy of a novel SGK1 inhibitor (EMD638683). EMD638683 was tested in vitro by determination of SGK1-dependent phosphorylation of NDRG1 (N-Myc downstream-regulated gene 1) in human cervical carcinoma HeLa-cells. In vivo EMD638683 (4460 ppm in chow, i.e. approx. 600 mg/kg/day) was administered to mice drinking tap water or isotonic saline containing 10% fructose. Blood pressure was determined by the tail cuff method, and urinary electrolyte (flame photometry) concentrations determined in metabolic cages. In vitro testing disclosed EMD638683 as a SGK1 inhibitor with an IC50 of 3 μM. Within 24 hours in vivo EMD638683 treatment significantly decreased blood pressure in fructose/saline-treated mice but not in control animals or in SGK1 knockout mice. EMD638683 failed to alter the blood pressure in SGK1 knockout mice. Following chronic (4 weeks) fructose/high salt treatment, additional EMD638683 treatment again decreased blood pressure. EMD638683 thus abrogates the salt sensitivity of blood pressure in hyperinsulinism without appreciably affecting blood pressure in the absence of hyperinsulinism. EMD638683 tended to increase fluid intake and urinary excretion of Na(+), significantly increased urinary flow rate and significantly decreased body weight.
EMD638683 could serve as a template for drugs counteracting hypertension in individuals with type II diabetes and metabolic syndrome.
血清和糖皮质激素诱导激酶1（SGK1）受盐皮质激素转录上调并被胰岛素激活。该激酶增强肾小管钠重吸收，并导致通过果糖或脂肪饮食诱导高胰岛素血症的小鼠在高盐饮食后血压升高。本研究描述了一种新型SGK1抑制剂（EMD638683）的体外和体内疗效。通过测定人宫颈癌HeLa细胞中SGK1依赖性的NDRG1（N-Myc下游调控基因1）磷酸化，在体外对EMD638683进行测试。在体内，将EMD638683（饲料中含量为4460 ppm，即约600 mg/kg/天）给予饮用自来水或含10%果糖的等渗盐水的小鼠。通过尾套法测定血压，并在代谢笼中测定尿电解质（火焰光度法）浓度。体外测试显示EMD638683是一种SGK1抑制剂，IC50为3 μM。在体内，EMD638683治疗24小时内显著降低了果糖/盐水处理小鼠的血压，但对对照动物或SGK1基因敲除小鼠无效。EMD638683未能改变SGK1基因敲除小鼠的血压。在慢性（4周）果糖/高盐处理后，额外的EMD638683治疗再次降低了血压。因此，EMD638683消除了高胰岛素血症中血压的盐敏感性，而在无高胰岛素血症时对血压无明显影响。EMD638683倾向于增加液体摄入量和尿钠排泄，显著增加尿流率并显著降低体重。
EMD638683可作为治疗II型糖尿病和代谢综合征患者高血压药物的模板。
