Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release
Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release
复制标题
DOI：
10.1681/asn.2008070740
复制
发表时间：
2009-05-01
影响因子：
13.6
通讯作者：
Peti-Peterdi, Janos
中科院分区：
文献类型：
--
作者：
Vargas, Sarah Laurin;Toma, Ildiko;Peti-Peterdi, Janos
肾小球器（JGA）的致密斑（MD）细胞是盐传感器，并产生旁分泌信号，控制肾血流、肾小球滤过和促高血压激素肾素的释放。我们假设最近鉴定的琥珀酸受体GPR 91存在于MID细胞中并调节肾素释放。使用免疫组织化学，我们确定了GPR 91在MID细胞的顶端质膜。用琥珀酸活化丝裂原活化蛋白激酶（MAPK; p38和细胞外信号调节激酶1/2）和环氧合酶2（考克斯-2）处理IMID细胞，并诱导前列腺素E-2的合成和释放，前列腺素E-2是一种有效的血管扩张剂和经典的肾素释放旁分泌介质。使用微灌注JGA和实时共聚焦荧光成像的奎纳克林标记的肾素颗粒，我们检测到显着的肾素释放响应管状琥珀酸（EC 50 350 μ M）。GPR 91基因缺失（GPR 91（-/-）小鼠）或MAPK或考克斯-2的药理学抑制阻断琥珀酸诱导的肾素释放。链脲佐菌素诱导的糖尿病引起肾皮质磷酸化p38、细胞外信号调节激酶1/2、考克斯-2和肾素含量的GPR 91依赖性上调。在野生型小鼠中，1周的盐消耗使血浆肾素活性增加了7倍，但在GPR 91（-/-）小鼠中仅增加了3.4倍。总之，MID细胞可以通过肾小管琥珀酸的积累和GPR 91信号传导（其涉及MAPK、考克斯-2的活化和前列腺素E-2的释放）来感知局部组织代谢的改变。这种机制可能是在健康和疾病中调节肾素释放和激活肾素-血管紧张素系统的组成部分。
Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) are salt sensors and generate paracrine signals that control renal blood flow, glomerular filtration, and release of the prohypertensive hormone renin. We hypothesized that the recently identified succinate receptor GPR91 is present in MID cells and regulates renin release. Using immunohistochemistry, we identified GPR91 in the apical plasma membrane of MID cells. Treatment of IMID cells with succinate activated Mitogen-activated protein kinases (MAPKs; p38 and extracellular signal-regulated kinases 1/2) and cyclooxygenase 2 (COX-2) and induced the synthesis and release of prostaglandin E-2, a potent vasodilator and classic paracrine mediator of renin release. Using microperfused JGA and real-time confocal fluorescence imaging of quinacrine-labeled renin granules, we detected significant renin release in response to tubular succinate (EC50 350 mu M). Genetic deletion of GPR91 (GPR91(-/-) mice) or pharmacologic inhibition of MAPK or COX-2 blocked succinate-induced renin release. Streptozotocin-induced diabetes caused GPR91-dependent upregulation of renal cortical phospho-p38, extracellular signal-regulated kinases 1/2, COX-2, and renin content. Salt depletion for 1 wk increased plasma renin activity seven-fold in wild-type mice but only 3.4-fold in GPR91(-/-) mice. In summary, MID cells can sense alterations in local tissue metabolism via accumulation of tubular succinate and GPR91 signaling, which involves the activation of MAPKs, COX-2, and the release of prostaglandin E-2. This mechanism may be integral in the regulation of renin release and activation of the renin-angiotensin system in health and disease.