Pathophysiological and Clinical Significance of Renal Prostanoid Receptors

前列腺素（PG）及其受体可能与各种肾脏疾病如糖尿病肾病和高血压有关。为了探讨前列腺素受体在肾脏中的作用，我们采用实验性疾病模型研究了体外培养的大鼠系膜细胞中前列腺素受体的表达及其功能意义，以及药物阻断对前列腺素受体的影响。PGE_2对肾小球系膜细胞增殖的作用呈双相性，当PGE_2浓度为0.10nM时，细胞增殖受到最大的刺激，细胞增殖通过EP_1受体被Ca动员所刺激，而通过EP_4受体被cAMP刺激所抑制。高糖条件下培养的肾小球系膜细胞生长增强，这种高糖诱导的系膜细胞增殖几乎完全被加入选择性EP_1拮抗剂所消除。在此条件下，PGE_2的产生增加，cAMP的产生增加， ...更多信息 结果表明，高糖条件下，EP_1和EP_4信号通路的失衡以及自身分泌PGE_2/EP_1系统的相对增强是促进细胞增殖的重要因素。类似地，这种EP_4信号减弱而EP_1信号增强的不平衡存在于易卒中的自发性高血压大鼠的系膜细胞中，并且可以解释这些细胞在培养物中高度增殖的性质的基础。为了阐明体内前列腺素类受体可能不平衡的作用，我们接下来在大鼠链脲佐菌素诱导的糖尿病肾病模型中检查EP_1阻断的效果。长期口服选择性EP_1拮抗剂可有效地改善糖尿病大鼠的组织和功能损害及蛋白尿。这些结果表明，肾脏前列腺素受体的异常可能是各种肾脏疾病的病理生理基础，用选择性配体调节肾脏前列腺素受体可能成为肾脏疾病治疗的新策略。少

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