Mechanisms Controlling Renin

肾素是血管紧张素II形成的限速酶步骤。CAMP刺激肾素释放 球旁(JG)细胞。钙(Ca)具有抑制作用，因为细胞外钙的增加抑制了肾素 释放，可能是通过增加细胞内钙。我们发现JG细胞表达钙敏感受体 (CASR)。此外，我们发现CaSR的激活减少了基础cAMP的产生和肾素的释放。我们的数据 提示CaSR的激活增加了细胞内的钙，抑制了腺苷的钙抑制异构体(V 降低cAMP，抑制肾素释放。相反，细胞外减少 CA应该使CaSR失活，增加cAMP的形成，从而刺激肾素的释放。此外，营地 被磷酸二酯酶(PDE)降解，其亚型PDE 1是钙依赖的，提示CaSR被激活 夸大cAMP的降解，减少肾素的释放。我们假设细胞外钙离子增加 激活JG细胞上的CaSR，从而增加细胞内钙。反过来，这又减少了难民营的产量 钙抑制的异构体腺苷环化酶V，并通过钙依赖的PDE 1促进cAMP的降解， 从而减少肾素的释放。这一假设将在4个目标中得到检验。目标一.假设：激活 CaSR通过生理性增加细胞外钙而增加细胞内钙从而抑制肾素 放手。目的II.假说：激活CaSR通过激活L型钙通道抑制肾素释放 刺激细胞内储存的钙释放。目的III.激活CaSR抑制腺酰环化酶V和 激活PDE-1，导致cAMP减少和肾素释放抑制。目标四.假设： 向粗大的升肢输送NaCI的增加将增加肾皮质的间质钙， 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在 培养和研究细胞内钙、钙通道、cAMP合成和降解及肾素的变化 放手。在体内，我们将研究皮质间质Ca、CaSR激活或 抑制cAMP的形成和肾素的分泌。这个项目与中心主题有关，因为肾素- 血管紧张素系统是一种肾旁分泌/自分泌系统，影响肾脏的血流、钠、钙和血液。 压力。这个项目的信息将与所有其他项目的信息整合在一起。它将使用所有 这些核心。我们的发现可能会从对高血压发病机制的新见解中引导出治疗高血压的新方法 调节肾素。

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.