权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pathophysiological and Clinical Significance of Renal Prostanoid Receptors

肾前列腺素受体的病理生理学和临床意义

基本信息

批准号：
11470217
负责人：
MUKOYAMA Masashi
金额：
$ 2.82万
依托单位：
Research Institute for Production Development
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Prostaglandins (PGs) and their receptors may be implicated in various renal disorders such as diabetic nephropathy and hypertension. To explore the roles of prostanoid receptors in the kidney, we studied their expression and functional significance in cultured mesangial cells as well as the effects of the pharmacological blockade using experimental disease models.Cultured rat mesangial cells expressed EP_1 and EP_4 subtypes among four PGE_2 receptors. PGE_2 exhibited a biphasic effect on proliferation of mesangial cells showing a maximal stimulation at 〜10 nM, and cell growth was stimulated via the EP_1 receptor by Ca mobilization, whereas it was inhibited through the EP_4 receptor by cAMP stimulation. Mesangial cells cultured under high glucose conditions showed augmented cell growth, and such high glucose-induced mesangial proliferation was almost completely abolished by the addition of selective EP_1 antagonists. In this condition, PGE_2 production was increased while cAMP productio … More n via EP_4 was significantly attenuated, indicating that the imbalance between EP_1 and EP_4 signaling with relatively augmented autocrjne PGE_2/EP_1 system is important for the enhanced proliferation under high glucose conditions. Similarly, such imbalance with attenuated EP_4 while enhanced EP_1 signaling was present in mesangial cells from stroke-prone spontaneously hypertensive rats and may explain the basis for highly proliferative nature of these cells in culture.To clarify a role of possible imbalance of prostanoid receptors in vivo, we next examined the effect of EP_1 blockade in a streptozotocin-induced diabetic nephropathy model in rats. Chronic oral administration of a selective EP_1 antagonist into diabetic rats effectively ameliorated the histological and functional impairment as well as proteinuria in diabetic rats. Furthermore, treatment with an EP_1 antagonist in spontaneously hypertensive rats resulted in the amelioration of hypertensive glomerular injuries.These results indicate that the abnormalities in renal prostanoid receptors may underlie the pathophysiology of various renal disorders, suggesting that the pharmacological modulation of the renal prostanoid receptors with selective ligands may become a novel therapeutic strategy in renal diseases. Less

前列腺素及其受体可能与多种肾脏疾病有关，如糖尿病肾病和高血压。为了探讨前列腺素受体在肾脏中的作用，我们通过实验疾病模型研究了前列腺素受体在培养肾系膜细胞中的表达和功能意义，以及药物阻断对肾系膜细胞的影响。培养的大鼠系膜细胞在4种PGE_2受体中表达EP_1和EP_4亚型。PGE_2对系膜细胞的增殖表现出双相作用，在~ 10 nM处刺激最大，Ca活化可通过EP_1受体刺激细胞生长，而cAMP刺激可通过EP_4受体抑制细胞生长。高糖条件下培养的系膜细胞生长增强，而选择性EP_1拮抗剂几乎完全消除了这种高糖诱导的系膜增殖。在高糖条件下，PGE_2的生成增加，cAMP的生成明显减少，EP_4介导的More n的生成明显减弱，说明EP_1和EP_4信号通路的不平衡与PGE_2/EP_1系统相对增强是高糖条件下细胞增殖增强的重要原因。同样，这种EP_4信号减弱而EP_1信号增强的不平衡也存在于卒中易发自发性高血压大鼠系膜细胞中，这可能解释了这些细胞在培养过程中具有高度增殖性质的基础。为了阐明体内前列腺素受体可能失衡的作用，我们接下来在链脲佐菌素诱导的大鼠糖尿病肾病模型中检测了EP_1阻断的作用。慢性口服选择性EP_1拮抗剂可有效改善糖尿病大鼠的组织学和功能损害以及蛋白尿。此外，用EP_1拮抗剂治疗自发性高血压大鼠可改善高血压肾小球损伤。这些结果表明，肾前列腺素受体的异常可能是多种肾脏疾病病理生理的基础，表明用选择性配体对肾前列腺素受体进行药理学调节可能成为肾脏疾病的一种新的治疗策略。少