肾小管上皮细胞钠-葡萄糖共转运体2(SGLT2)-环氧-二十碳-三烯酸(EETs)调节血糖代谢和血压的新靶点

Type 2 diabetes complicated with hypertension is very common, and it is of high risk. It is pivotal to manage the blood pressure for the reduction of cardiovascular morbidity and mortality in diabetic patients. Previous data indicated that the kidney played an important role in the pathogenesis of type 2 diabetes complicated with hypertension. Our and others’ data indicated that renal tubular epithelial cell sodium glucose cotransporter 2 (SGLT2) inhibitor significantly improved glucose metabolism and reduced blood pressure in patients with diabetes, and 11,12-EET markedly inhibited SGLT2 expression induced by insulin treatment; In addition, soluble epoxide hydrolase (sEH) inhibitor TPPU significantly improved glucose metabolism and reduced blood pressure in diabetic mice complicated with hypertension. It is hypothesized that EETs improved glucose metabolism and reduced blood pressure via reduced the expression and activity of SGLT2 of renal tubular epithelial cell in diabetic mice complicated with hypertension. In this project, the roles and mechanisms of sEH knockout or sEH inhibitor TPPU and endothelial specific CYP2J2 transgene on glucose metabolism and blood pressure regulation will be investigated in diabetic mice complicated with hypertension, and moreover, the effects and mechanisms of EETs on SGLT2 expression in renal tubular epithelial cell will also be explored in vitro. SGLT2 as a new target for EETs to regulate glucose metabolism and blood pressure will be further identified through this project.

2型糖尿病合并高血压十分常见，危害巨大，控制糖尿病病人的血压是减少致残率和致死率的关键。肾脏在2型糖尿病合并高血压的发病过程中具有重要作用。钠-葡萄糖共转运体2(SGLT2)抑制剂显著降低糖尿病患者的血糖和血压，预实验结果提示11,12-环氧-二十碳-三烯酸(11,12-EET)显著抑制了SGLT2的表达，可溶性表氧化水解酶(sEH)抑制剂TPPU显著改善了糖尿病合并高血压模式动物的血糖代谢和血压。因此，我们设想EETs通过抑制SGLT2的表达起到改善糖尿病合并高血压模式动物血糖代谢和降低血压的作用。本项目拟在高脂和高钠饮食诱导的糖尿病合并高血压模式动物中，研究sEH基因敲除或者其抑制剂TPPU和CYP2J2内皮细胞特异性转基因改善模式动物血糖代谢和降低血压的作用及其机制；深入研究EETs抑制SGLT2表达的作用及其机制。通过本项目研究将阐明SGLT2是EETs调节血糖代谢和血压的新靶点。

2型糖尿病合并高血压十分常见，危害巨大，控制糖尿病病人的血压是减少致残率和致死率的关键。肾脏在2型糖尿病合并高血压的发病过程中具有重要作用。钠-葡萄糖共转运体2(SGLT2)抑制剂显著降低糖尿病患者的血糖和血压，本项目发现环氧-二十碳-三烯酸(EETs)显著抑制了SGLT2的表达，可溶性表氧化水解酶(sEH)抑制剂TPPU显著改善了糖尿病合并高血压模式动物的血糖代谢和血压。其具体机制为小分子活性物质EETs（主要是14, 15-EET）通过抑制肾脏IKKα/β/NF-κB炎症通路的激活，进而抑制NF-κB与SGLT2启动子区域的结合，阻断肾脏SGLT2的转录和表达，从而促进钠和葡萄糖的排泄，降低高血压合并糖尿病模式小鼠的血压和血糖，改善胰岛素抵抗。提示增加EETs 的含量可能是糖尿病合并高血压未来治疗的方向，通过本项目研究进一步明确了EETs调节血压和血糖的作用及其机制，从而为利用EETs来探索糖尿病合并高血压新的防治策略奠定了重要的理论基础。