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， 肾小球（JG）细胞。钙（Ca）是抑制性的，因为细胞外Ca的增加抑制了肾素 释放，可能是通过增加细胞内Ca。我们发现JG细胞表达钙敏感受体， （CaSR）。此外，我们发现CaSR激活减少基础cAMP产生和肾素释放。我们的数据 提示CaSR激活增加细胞内Ca，抑制腺苷酸的Ca-可吸收亚型（V）， 在JG细胞中的环化酶，降低cAMP和抑制肾素释放。相反，细胞外 钙应该抑制CaSR，增加cAMP的形成，从而刺激肾素的释放。此外，cAMP 被磷酸二酯酶（PDE）降解，并且亚型PDE 1是Ca依赖性的，表明CaSR激活 加剧cAMP降解，减少肾素释放。我们假设细胞外Ca ~（2+）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， 钙依赖性同工型腺苷酸环化酶V并通过钙依赖性PDE 1增强cAMP降解， 从而减少肾素释放。这一假设将在4个目标中进行检验。艾姆岛假设：激活 CaSR通过细胞外Ca的生理性增加而增加细胞内Ca，从而抑制肾素 release. Aim II.假设：CaSR的激活通过激活L型Ca通道抑制肾素释放， 刺激细胞内钙释放。Aim III. CaSR的激活抑制腺苷酸环化酶V和腺苷酸环化酶V的表达。 激活PDE 1，导致cAMP减少和肾素释放抑制。目标四。假设： 增加向粗升支输送NaCl将增加肾皮质中的间质Ca， 激活JG细胞上的CaSR，这反过来又会抑制肾素。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 release.在体内，我们将研究皮质间质Ca，CaSR激活或 抑制、cAMP形成和肾素分泌。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，影响肾灌注、Na、Ca和血液 压力该项目的信息将与所有其他项目的信息相结合。它将使用所有 核心。我们的发现可能会导致新的高血压治疗方法， 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.