Intestinal Peptides Involved in Volume Homeostasis

参与容量稳态的肠肽

• 批准号: 7475209
• 负责人: MICHAEL F. GOY
• 金额: $ 38.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475209
• 关键词: Ablation; Accounting; Acute; Address; Affect; Agonist; Amino Acids; Animals; Antibodies; Biological; Blood Pressure; Data; Dependency; Depth; Diagnosis; Disease; Diuresis; Diuretics; Dose; Endocrine; Excretory function; Family; Genes; Guanylate Cyclase; Homeostasis; Hormonal; Hormones; Immunoassay; Infusion procedures; Ingestion; Intestines; Kidney; Ligands; Link; Liquid substance; Liver; Measures; Mediating; Mediator of activation protein; Melanocytic nevus; Messenger RNA; Methods; Modeling; Mole the mammal; Mosses; Mus; Natriuresis; Natriuretic Agents; Neurons; Operative Surgical Procedures; Oral; Organ; Participant; Peptides; Phenotype; Physiological; Physiology; Plasma; Play; Process; Property; Proteins; Proteomics; Rate; Rattus; Research Personnel; Role; Role playing therapy; Sodium; Sodium Chloride; Structure; System; Testing; Time; Tissues; Urine; Work; base; concept; hemodynamics; in vivo; intravenous administration; knockout animal; member; novel; peptide hormone; prevent; programs; prouroguanylin; receptor; research study; response; salt intake; saluretic; solute; urinary; uroguanylin

DESCRIPTION (provided by applicant): The natriuresis that follows ingestion of a solute load is more rapid than the natriuresis that occurs when an equivalent solute load is given intravenously, due to the operation of an entero-renal endocrine axis. Efforts to identify the hormonal mediator(s) of this axis have recently focused on uroguanylin (UGnn), a 17 amino acid peptide that activates guanylate cyclase-C (GC-C), a member of the ligand-activated family of receptor/guanylate cyclases. Key features of UGnn include the following: (1) its precursor (proUGn) is expressed primarily in the intestine, (2) UGnn circulates in the plasma, (3) infusion of exogenous UGnn induces renal natriuresis and diuresis, and (4) ablation of the uroguanylin gene elevates blood pressure and markedly decreases the rate of excretion of orally-delivered salt. However, two observations argue against a role for UGnn in salt homeostasis. (1) UGnn is a relatively ineffective natriuretic agent, inducing small (2 - 4-fold) urinary responses, and those only at supra-normal concentrations. (2) GC-C, the only known receptor for UGnn, is barely expressed in the kidney. Furthermore, GC-C knockout animals lack the elevated blood pressure seen in mice after ablation of the uroguanylin gene. Thus, although an intact uroguanylin gene is necessary for efficient excretion of oral salt, the known properties of UGnn and GC-C are inadequate to account for the phenotype of uroguanylin knockout animals. The preliminary data presented in this application provide an explanation for this paradox. We have found that intravenous infusion of proUGn into anesthetized rats provokes dramatic (30-fold) increases in renal Na excretion-though, like others, we detect only small responses mediated by GC-C. In addition, using a newly-developed immunoassay for proUGn, we have shown that levels of endogenous proUGn in plasma respond to dietary salt intake. Thus, we propose that either proUGn itself, or a metabolite derived from it (but distinct from UGnn), is the true natriuretic link between the gut and the kidney. Experiments described in our application will test and extend this hypothesis, and may suggest uses for proUGn in the diagnosis or treatment of diseases in which salt and/or fluid homeostasis is deranged.

描述（由申请人提供）：摄入溶质负荷后的纳特里列赛比在静脉内给出等效溶质负载时发生的纳特里雷仪更快，这是由于肠道内分泌轴的操作而静脉内给予的。鉴定该轴激素介质的努力最近集中在泌尿素蛋白（UGNN）上，这是一种17个氨基酸肽，该氨基酸肽激活了鸟苷酸环化酶-C（GC-C），GC-C-C（GC-C）是受体/鸟苷酸环酶的配体激活家族的成员。 UGNN的关键特征包括以下内容：（1）其前体（prougn）主要在肠道中表达，（2）UGNN在血浆中循环，（3）输注外源性UGNN肾脏肾上腺素和diuresis和diuresis和diuresis，以及（4）（4）在尿液中降低了高度降低血液的率，并降低了高度降低的率。 盐。但是，两个观察结果反对UGNN在盐稳态中的作用。 （1）UGNN是一种相对无效的亚钠剂，诱导小（2-4倍）尿反应，而仅处于超正常浓度。 （2）GC-C是唯一已知的UGNN受体，在肾脏中几乎没有表达。此外，GC-C基因敲除动物缺乏消融泌尿蛋白苷基因后小鼠的血压升高。因此，尽管完整的泌尿素蛋白基因对于有效排泄口服盐是必需的，但UGNN和GC-C的已知特性不足以说明尿素蛋白基因敲除动物的表型。本应用程序中提供的初步数据为此悖论提供了解释。我们发现，将普鲁格静脉注射到麻醉大鼠中会引起肾脏Na排泄的戏剧性增加（30倍），尽管与其他人一样，我们仅检测到GC-C介导的小反应。此外，使用新发达的免疫测定法对Prougn进行，我们已经表明，血浆中的内源性PROUGN水平会响应饮食盐的摄入。因此，我们提出，肠道和肾脏之间的真正纳地尿连接是普鲁格本身或从中衍生出的代谢产物（但与ugnn不同）。我们的应用中描述的实验将检验和扩展此假设，并可能建议将Prougn用于诊断或治疗盐和/或液体稳态的疾病。