Mechanisms Controlling Renin

肾素的控制机制

基本信息

批准号：
8376985
负责人：
WILLIAM H BEIERWALTES
金额：
$ 37.47万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

项目摘要

Renin is the rate-limiting enzymatic step in angiotensin II formation. cAMP stimulates renin release from juxtaglomerular (JG) cells. Calcium (Ca) is inhibitory, as increased extracellular Ca suppresses renin release, presumably by increasing intracellular Ca. We found that JG cells express Ca-sensing receptors (CaSR). Further, we found CaSR activation reduces basal cAMP production and renin release. Our data suggest CaSR activation increases intracellular Ca, suppressing the Ca-inhibitable isoform (V) of adenylyl cyclase in the JG cells, decreasing cAMP and inhibiting renin release. Conversely, decreased extracellular Ca should inactivate CaSR, increasing cAMP formation and thus stimulating renin release. In addition, cAMP is degraded by phosphodiesterases (PDE), and isoform PDE 1 is Ca dependent, suggesting CaSR activation exaggerates cAMP degradation, reducing renin release. We hypothesize that increased extracellular Ca activates CaSR on JG cells, thereby increasing intracellular Ca. This, in turn, reduces cAMP production by the Ca-inhibitable isoform adenylyl cyclase V and augments cAMP degradation by the Ca-dependent PDE 1, thereby reducing renin release. This hypothesis will be tested in 4 aims. Aim I. Hypothesis: Activation of CaSR by physiological increases in extracellular Ca increases intracellular Ca and thus inhibits renin release. Aim II. Hypothesis: Activation of CaSR inhibits renin release by activating L-type Ca channels and stimulating Ca release from intracellular stores. Aim III. Activation of CaSR inhibits adenylyl cyclase V and activates PDE 1, both resulting in decreased cAMP and inhibition of renin release. Aim IV. Hypothesis: Increases in delivery of NaCI to the thick ascending limb will increase interstitial Ca in the renal cortex, activating CaSR on JG cells, which will in turn suppress renin. We will activate or inhibit JG cell CaSR in culture and study changes in intracellular Ca, Ca channels, cAMP synthesis and degradation, and renin release. In vivo, we will study acute and chronic changes in cortical interstitial Ca, CaSR activation or inhibition, cAMP formation and renin secretion. This project relates to the central theme because the renin- angiotensin system is a renal paracrine/autocrine system influencing renal perfusion, Na, Ca and blood pressure. The information from this project will be integrated with that from all other projects. It will use all of the cores. Our findings may lead to new treatments of hypertension from new insights into mechanisms that regulate renin.

肾素是血管紧张素 II 形成中的限速酶促步骤。 cAMP 刺激肾素释放肾小球旁 (JG) 细胞。钙 (Ca) 具有抑制作用，因为细胞外 Ca 的增加会抑制肾素释放，可能是通过增加细胞内 Ca。我们发现JG细胞表达Ca2+敏感受体（钙SR）。此外，我们发现 CaSR 激活会减少基础 cAMP 的产生和肾素的释放。我们的数据表明 CaSR 激活增加细胞内 Ca，抑制腺苷酸的 Ca 抑制亚型 (V) JG 细胞中的环化酶，降低 cAMP 并抑制肾素释放。相反，细胞外 Ca 应该使 CaSR 失活，增加 cAMP 形成，从而刺激肾素释放。此外，环磷酸腺苷被磷酸二酯酶 (PDE) 降解，同种型 PDE 1 具有 Ca 依赖性，表明 CaSR 激活加剧 cAMP 降解，减少肾素释放。我们假设细胞外 Ca 增加激活 JG 细胞上的 CaSR，从而增加细胞内 Ca。这反过来又减少了 cAMP 的产生 Ca 抑制同种型腺苷酸环化酶 V 并通过 Ca 依赖性 PDE 1 增强 cAMP 降解，从而减少肾素释放。该假设将在 4 个目标中进行检验。目标 I. 假设：激活 CaSR 通过生理性增加细胞外 Ca 增加细胞内 Ca，从而抑制肾素发布。目标二。假设：CaSR 的激活通过激活 L 型 Ca 通道抑制肾素释放，刺激细胞内储存的 Ca 释放。目标三。 CaSR 的激活抑制腺苷酸环化酶 V 和激活 PDE 1，导致 cAMP 减少并抑制肾素释放。目标四。假设：向粗升肢输送 NaCl 的增加将增加肾皮质间质 Ca 的含量，激活 JG 细胞上的 CaSR，进而抑制肾素。我们将激活或抑制JG细胞CaSR 培养和研究细胞内 Ca、Ca 通道、cAMP 合成和降解以及肾素的变化发布。在体内，我们将研究皮质间质 Ca、CaSR 激活或的急性和慢性变化。抑制、cAMP 形成和肾素分泌。这个项目与中心主题相关，因为肾素血管紧张素系统是影响肾灌注、Na、Ca和血液的肾旁分泌/自分泌系统压力。该项目的信息将与所有其他项目的信息整合。它将使用所有核心。我们的发现可能会从对机制的新见解中带来高血压的新治疗方法调节肾素。