Arginine Uptake Mechanisms Regulate Nitric Oxide in the Renal Vasculature

精氨酸摄取机制调节肾脉管系统中的一氧化氮

• 批准号: 7671452
• 负责人: David L. Mattson
• 金额: $ 25.24万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671452
• 关键词: Address; Affect; Amino Acids; Animals; Antisense Oligonucleotides; Arginine; Biochemical; Biological Assay; Blood Pressure; Blood Vessels; Blood flow; Cause of Death; Data; Defect; Duct (organ) structure; Electrolytes; Endothelial Cells; Epithelial Cells; Excretory function; Experimental Animal Model; Homeostasis; Hypertension; Immunohistochemistry; In Vitro; Kidney; Laboratories; Liquid substance; Mediating; Methodology; Methods; Microdissection; Modeling; Molecular; Morbidity - disease rate; Mus; Nitric Oxide; Nitric Oxide Synthase; Peripheral Resistance; Physiological; Play; Preparation; Production; Protein Isoforms; Publishing; Regulation; Renal function; Research; Role; Small Interfering RNA; Techniques; Testing; Tubular formation; Vascular Endothelial Cell; Vascular resistance; Work; in vivo; insight; kidney vascular structure; neutralizing antibody; novel; research study; uptake

DESCRIPTION (provided by applicant): Nitric oxide (NO) regulates arterial blood pressure and kidney function by influencing systemic vascular resistance and fluid and electrolyte homeostasis. Despite the large amount of research on this subject, the factors important in the regulation of NO production in the kidney have not been clearly defined. Previous work from our laboratory demonstrated the importance of L-Arginine (L-Arg) uptake mechanisms in renal epithelial cells. Exciting new results from our laboratory indicate that cellular uptake of L-Arg, the substrate for NO synthase, is also a critical modulator of NO production in renal vascular endothelial cells. L-Arg uptake is therefore also an important regulator of renal vascular resistance with resulting effects on kidney excretory function. New data will be presented indicating that mechanisms of L-Arg transport have important effects on NO production and NO-dependent function in the renal vasculature. Using these novel data as a rationale and a unique integrative experimental approach, we will define the role of the L-Arg transporters in the regulation of renal vascular function in vitro and in vivo to provide an understanding of the importance of this physiological regulator of NO production. Experiments will test the General Hypothesis that cellular L-arginine uptake by y+ and y+L transporters in endothelial cells of the renal vasculature mediates the production of NO by altering the availability of NOS substrate in vivo and plays a critical role in the regulation of renal function as well as fluid and electrolyte homeostasis. This hypothesis will be addressed in three specific aims. Specific Aim 1 will utilize unique cellular and molecular techniques to identify the L-Arg uptake mechanisms and transporters in renal blood vessels. Aim 2 will employ novel methodology to determine the functional importance of these transporters in the renal vasculature on NO production and NO-dependent function both in vitro and in vivo in normal and diseased animals. Experiments in Aim 3 will then make use of genetically manipulated mice to determine which NOS isoform is affected by cellular L-Arg uptake mechanisms. This novel combination of experimental methods will be used to elucidate the important role of L-Arg transport in the regulation of renal vascular resistance and kidney function. The results of these studies may provide important insight into the causes of hypertension and vascular-related complications that are a leading cause of death and morbidity in the US.

描述（由申请人提供）：一氧化氮（NO）通过影响全身血管耐药性以及液体和电解质稳态来调节动脉血压和肾功能。尽管对该主题进行了大量研究，但在调节肾脏中没有生产的因素方面尚未明确定义。我们实验室的先前工作表明，肾上皮细胞中L-精氨酸（L-ARG）摄取机制的重要性。我们实验室的令人兴奋的新结果表明，L-Arg的细胞摄取是NO合酶的底物，也是肾血管内皮细胞无生产的关键调节剂。因此，L-Arg摄取也是肾血管耐药性的重要调节剂，对肾脏排泄功能产生影响。将提供新数据，表明L-ARG运输的机制对NO生产和无依赖性功能具有重要影响。我们将使用这些新的数据作为基本原理和独特的综合实验方法，我们将定义L-ARG转运蛋白在体外和体内调节肾血管功能调节中的作用，以提供对这种无生产生理调节剂的重要性的理解。实验将检验以下一般假设：肾脏脉管系统的Y+和Y+ L转运蛋白的细胞L-精氨酸摄取通过改变体内NOS底物的可用性，并在体内介导NO的产生，并在调节肾功能以及流体和电解质托管机构的调节中起关键作用。该假设将以三个具体目标解决。具体目标1将利用独特的细胞和分子技术来识别肾血管中的L-Arg摄取机制和转运蛋白。 AIM 2将采用新颖的方法来确定这些转运蛋白在肾脏脉管系统中的功能重要性，而在正常动物和患病动物中，在没有生产和无依赖性功能的情况下，无依赖性功能。然后，AIM 3中的实验将利用遗传操纵的小鼠来确定哪些NOS同工型受细胞L-Arg摄取机制的影响。实验方法的这种新型组合将用于阐明L-ARG转运在调节肾血管抗性和肾功能中的重要作用。这些研究的结果可能会为高血压和血管相关并发症的原因提供重要的见解，这是美国的主要死亡和发病率的主要原因。