内皮细胞前列腺素E2受体4亚型（EP4）在血管紧张素II诱导的慢性肾损伤中的作用和机制

Chronic kidney disease（CKD） is one of the most prevalent medical conditions in China. Hypertension is a key pathogenic factor that contributes to the deterioration of kidney，the majority of patients accompany with renin angiotensin system activation. Prostaglandin E2 receptor 4 subtype —EP4 is widely expressed in the kidney and blood vessels, and plays an important role in regulation of renal water reabsorption and blood pressure. Our previous study showed that endothelial cell-specific EP4 knockout mice (EC-EP4-/-) aggravated angiotensin II induced renal glomerular sclerosis and inflammation. EP4 agonist inhibited the activation of NLRP3/ASC-caspase1-IL1β pathway induced by AngII in cultured endothelial cells. Therefore, by using mice with specific deletion of EP4 in endothelial cells，we will elucidate the role of EP4 in renal endothelial cells. We anticipate that endothelial EP4 exerts anti-inflammatory and anti-fibrosis effect in AngII-associated renal injury through the activation of the cAMP-PKA pathway and the blockade of the NLRP3/ ASC-caspase1-IL1β pathway. This study may extend our knowledge of the molecular mechanisms of CKD induced by AngII and help to develop novel therapeutic drugs to treat chronic kidney disease.

慢性肾脏疾病是一种严重危害人类健康的重大疾病，其中高血压是主要的致病原因之一，且多伴肾素—血管紧张素系统激活。前列腺素E2受体4亚型(EP4)在肾脏和血管广泛表达，并且在肾脏水盐代谢和血压调节中有重要作用。我们前期研究发现，内皮细胞特异性EP4缺陷小鼠显著加重血管紧张素II（AngII）诱导的肾小球硬化和炎症。体外研究发现激活内皮细胞EP4可以抑制AngII引发的炎性小体通路（NLRP3-caspase1-IL1β）的激活。本项目拟使用内皮细胞EP4特异性缺陷小鼠，从整体动物和培养细胞水平验证我们提出的肾脏内皮细胞EP4通过cAMP-PKA通路抑制炎性小体通路激活，缓解由AngII诱导的肾脏炎症和纤维化进程的假说。本课题的开展将有助于阐明EP4 在AngII介导的慢性肾损伤中的作用及机制，为评估EP4作为高血压相关慢性肾脏疾病的治疗提供新思路和新靶点。