EDRF CONTROL OF RENAL FUNCTION

内皮源性舒张因子（EDRF），化学性质类似于 与一氧化氮相同，有助于维持正常血压， 扩张血管 L-精氨酸，EDRF的合成前体， 正常血压在达尔盐敏感的大鼠模型， 高血压，这表明EDRF信号传导的缺陷可能导致 高血压 最近的研究表明，EDRF不仅调制 肾血流动力学，但也改变肾钠排泄。 这 提供了另一种机制，通过这种机制，EDRF信号的缺陷可能导致 到高血压 然而，EDRF信号的细胞起源， EDRF在盐转运中的作用是未知的。 EDRF受体是 异二聚体可溶性鸟苷酸环化酶。 两个亚基（α 1和β 1） 广泛分布，可能在血管中， 血管舒张 最近，一种新的可溶性鸟苷酸环化酶亚基（β 2） 被发现优先在肾脏中表达。 其确切 位置和功能未知。 该项目的长期目标 是确定EDRF在肾脏盐和水转运中的作用。 我们 我们将研究以下目标：在目标1中，我们将本地化， 表征肾单位特定部分的EDRF受体， 使用cGMP积累和mRNA测定的肾脉管系统 在显微解剖的小管和血管中表达。 在目标2中， 将使用分离的小管定位EDRF产生的位点， 血管 我们将确定EDRF是否参与内部或内部- 蜂窝通信 目标3将涉及EDRF 调节体外离体灌注的钠和水转运 小管 我们将确定哪种膜和哪种转运蛋白是 受影响的目标 在目标4中，我们将克隆，表达和表达 表征肾脏中表达的其他EDRF受体亚基。 我们 有初步证据表明，α 1和β 1是表达在 肾血管系统，而只有β 2在肾小管中表达。 以来 EDRF受体是异源二聚体，这表明存在新的 EDRF受体亚单位（α x）。 更全面地了解EDRF 该通路可能允许开发新的高血压疗法。

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.