EDRF CONTROL OF RENAL FUNCTION

内皮衍生松弛因子(EDRF)，化学上类似于 与一氧化氮相同，通过以下方式帮助维持正常血压 扩张血管。L-精氨酸，EDRF的合成前体， 达尔盐敏模型大鼠血压正常化 高血压，表明EDRF信号的缺陷可能导致 高血压。最近的研究表明，EDRF不仅可以调节 肾脏血流动力学，但也改变肾脏的钠排泄。这 提供EDRF信令中的缺陷可能导致的另一种机制 到高血压。然而，EDRF信号的细胞起源，以及 EDRF在盐分运输中的作用尚不清楚。EDRF受体是 异二聚体可溶性鸟苷酸环化酶。两个亚基(α1和β1) 分布广泛，大概存在于它们所在的血管中 血管扩张。最近，一种新的可溶性鸟苷酸环化酶亚基(Beta2) 发现了在肾脏优先表达的基因。它的确切位置 位置和功能尚不清楚。这个项目的长期目标是 目的是确定EDRF在肾脏盐分和水转运中的作用。我们 将调查以下目标：在目标1中，我们将本地化和 鉴定肾单位和肾单位特定部位的EDRF受体 肾血管系统中cGMP积聚和mRNA的检测 在显微解剖的小管和血管中表达。在目标2中，我们 将使用隔离小管本地化EDRF生产场所 血管。我们将确定EDRF是否参与内部或内部 蜂窝通信。目标3将介绍EDRF的站点 体外灌流对钠和水转运的调节作用 小管。我们将确定哪种膜和哪种运输器是 受影响的目标。在目标4中，我们将克隆、表达和药理 鉴定肾脏中表达的其他EDRF受体亚单位。我们 有初步证据表明alpha1和beta1在 肾血管构筑，而β2仅在肾小管表达。自.以来 EDRF受体是异二聚体，这表明存在一种新的 EDRF受体亚单位(α)。对EDRF有更全面的了解 通路可能使高血压新疗法的开发成为可能。

Endothelium-derived relaxing factor (EDRF), chemically similar to identical to nitric oxide, helps maintain normal blood pressure by dilating blood vessels. L-arginine, the synthetic precursor of EDRF, normalizes blood pressure in the Dahl salt-sensitive rat model of hypertension, suggesting that defects in EDRF signalling could lead to hypertension. Recent studies have shown that EDRF not only modulates renal hemodynamics, but also alters renal sodium excretion. this provides another mechanism by which defects in EDRF signalling could lead to hypertension. However, the cellular origins of the EDRF signal, and the roles of EDRF in salt transport are unknown. EDRF receptors are heterodimeric soluble guanylyl cyclases. Two subunits (alpha1 and beta1) are widely distributed, presumably in blood vessels where they mediate vasodilation. Recently, a new soluble guanylyl cyclase subunit (beta2) was found which is preferentially expressed in the kidney. Its exact location and function are unknown. the long term goal of this project is to determine the role of EDRF in renal salt and water transport. We will investigate the following aims: In Aim 1, we will localize and characterize the EDRF receptors to specific portions of the nephron and renal vasculature using assays for both cGMP accumulation and mRNA expression in microdissected tubules and blood vessels. In Aim 2, we will localize the sites of EDRF production using isolated tubules and blood vessels. We will determine if EDRF is involved in intra- or inter- cellular communication. Aim 3 will address the sites at which EDRF modulates sodium and water transport in in vitro isolated perfused tubules. We will determine which membrane and which transporter is the affected target. In Aim 4, we will clone, express, and pharmacologically characterize other EDRF receptor subunits expressed in the kidney. We have preliminary evidence that alpha1 and beta1 are expressed in the renal vasculature, while only beta2 is expressed in renal tubules. Since EDRF receptors are heterodimers, this suggests the existence of a new EDRF receptor subunit (alphax). More complete knowledge of the EDRF pathway may allow the development of new therapies for hypertension.