Breyer M D, Breyer R M
Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Annu Rev Physiol. 2001;63:579-605. doi: 10.1146/annurev.physiol.63.1.579.
Renal cyclooxygenase 1 and 2 activity produces five primary prostanoids: prostaglandin E2, prostaglandin F2alpha, prostaglandin I2, thromboxane A2, and prostaglandin D2. These lipid mediators interact with a family of distinct G protein-coupled prostanoid receptors designated EP, FP, IP, TP, and DP, respectively, which exert important regulatory effects on renal function. The intrarenal distribution of these prostanoid receptors has been mapped, and the consequences of their activation have been partially characterized. FP, TP, and EP1 receptors preferentially couple to an increase in cell calcium. EP2, EP4, DP, and IP receptors stimulate cyclic AMP, whereas the EP3 receptor preferentially couples to Gi, inhibiting cyclic AMP generation. EP1 and EP3 mRNA expression predominates in the collecting duct and thick limb, respectively, where their stimulation reduces NaCl and water absorption, promoting natriuresis and diuresis. The FP receptor is highly expressed in the distal convoluted tubule, where it may have a distinct effect on renal salt transport. Although only low levels of EP2 receptor mRNA are detected in the kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2 receptor exhibit salt-sensitive hypertension, suggesting that this receptor may also play an important role in salt excretion. In contrast, EP4 receptor mRNA is predominantly expressed in the glomerulus, where it may contribute to the regulation of glomerular hemodynamics and renin release. The IP receptor mRNA is highly expressed near the glomerulus, in the afferent arteriole, where it may also dilate renal arterioles and stimulate renin release. Conversely, TP receptors in the glomerulus may counteract the effects of these dilator prostanoids and increase glomerular resistance. At present there is little evidence for DP receptor expression in the kidney. These receptors act in a concerted fashion as physiological buffers, protecting the kidney from excessive functional changes during periods of physiological stress. Nonsteroidal anti-inflammatory drug (NSAID)-mediated cyclooxygenase inhibition results in the loss of these combined effects, which contributes to their renal effects. Selective prostanoid receptor antagonists may provide new therapeutic approaches for specific disease states.
肾环氧化酶1和2的活性产生五种主要的前列腺素：前列腺素E2、前列腺素F2α、前列腺素I2、血栓素A2和前列腺素D2。这些脂质介质分别与一组不同的G蛋白偶联前列腺素受体相互作用，这些受体分别称为EP、FP、IP、TP和DP，它们对肾功能发挥重要的调节作用。这些前列腺素受体的肾内分布已被绘制出来，并且它们激活后的后果也已部分得到阐明。FP、TP和EP1受体优先与细胞内钙的增加偶联。EP2、EP4、DP和IP受体刺激环磷酸腺苷（cAMP），而EP3受体优先与Gi偶联，抑制cAMP的生成。EP1和EP3的信使核糖核酸（mRNA）表达分别在集合管和髓袢升支粗段占主导地位，在这些部位它们的刺激会减少氯化钠和水的重吸收，促进尿钠排泄和利尿。FP受体在远曲小管中高度表达，在那里它可能对肾盐转运有独特的作用。虽然在肾脏中仅检测到低水平的EP2受体mRNA，并且其确切的肾内定位尚不确定，但EP2受体靶向敲除的小鼠表现出盐敏感性高血压，这表明该受体可能在盐排泄中也起重要作用。相反，EP4受体mRNA主要在肾小球中表达，在那里它可能有助于调节肾小球血流动力学和肾素释放。IP受体mRNA在肾小球附近、入球小动脉中高度表达，在那里它也可能扩张肾小动脉并刺激肾素释放。相反，肾小球中的TP受体可能抵消这些舒张性前列腺素的作用并增加肾小球阻力。目前几乎没有证据表明肾脏中存在DP受体表达。这些受体以协同的方式作为生理缓冲剂起作用，在生理应激期间保护肾脏免受过度的功能变化影响。非甾体抗炎药（NSAID）介导的环氧化酶抑制导致这些联合作用丧失，这促成了它们的肾脏效应。选择性前列腺素受体拮抗剂可能为特定疾病状态提供新的治疗方法。
