Mechanisms Controlling Renin

肾素的控制机制

• 批准号: 7595342
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595342
• 关键词: Acute; Adenylate Cyclase; Agonist; Angiotensin II; Blood Pressure; Calcium; Calcium Channel; Calcium-Sensing Receptors; Cells; Chronic; Coupling; Cyclic AMP; Data; Dominant-Negative Mutation; Equilibrium; Fluorescence; Furosemide; In Vitro; Juxtaglomerular Cell; Kidney; L-Type Calcium Channels; Lead; Limb structure; Measures; Mediating; Perfusion; Physiological; Preparation; Production; Protein Isoforms; Receptor Activation; Renin; Renin-Angiotensin System; Role; Sodium; Testing; Thick; Transference; autocrine; blood pressure regulation; extracellular; hypertension treatment; in vivo; inhibitor/antagonist; insight; interstitial; kidney cortex; novel; paracrine; phosphodiesterase V; phosphoric diester hydrolase; prevent; receptor; response; sensor

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形成的限速酶促步骤。营地刺激肾素释放 并置（JG）细胞。钙（CA）是抑制性的，因为增加细胞外CA会抑制肾素 释放，大概是通过增加细胞内Ca的释放。我们发现JG细胞表达了CA敏感受体 （CASR）。此外，我们发现CASR激活减少了基础营地的生产和肾素释放。我们的数据 建议CASR激活增加细胞内Ca，从而抑制腺苷的Ca抑制同工型（V） JG细胞中的循环酶，减少营地并抑制肾素释放。相反，细胞外减少 CA应灭活CASR，增加营地形成，从而刺激肾素释放。此外，营地 被磷酸二酯酶（PDE）降解，同工型PDE 1依赖于CA，表明CASR激活 夸大营地退化，减少了肾素的释放。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。反过来，这减少了营地的生产 CA可抑制的同工型腺苷酸环化酶V和CA依赖性PDE 1的cAMP降解， 从而减少肾素释放。该假设将以4个目标进行检验。 Aim I.假设：激活 CASR通过生理增加的细胞外Ca增加了细胞内Ca，从而抑制肾素 发布。目标II。假设：CASR的激活通过激活L型CA通道和 刺激CA从细胞内存储中释放。目标三。 CASR的激活抑制腺苷酸环化酶V和 激活PDE 1，均导致CAMP减少和抑制肾素释放。目标IV。假设： NACI向厚升肢的递送增加将增加肾皮质中的间隙Ca， 激活JG细胞上的CASR，这又会抑制肾素。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 发布。在体内，我们将研究皮质间质CA的急性和慢性变化，CASR激活或 抑制作用，营地形成和肾素分泌。该项目与中心主题有关，因为肾素 - 血管紧张素系统是影响肾脏灌注的肾脏旁分泌/自分泌系统Na，Ca和血液 压力。该项目的信息将与所有其他项目的信息集成在一起。它将使用所有 核心。我们的发现可能会导致新见解的新疗法 调节肾素。