Nitric Oxide Synthase Isoforms in the Kidney

肾脏中的一氧化氮合酶亚型

• 批准号: 7851385
• 负责人: Jennifer S Pollock
• 金额: $ 36.75万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851385
• 关键词: Acute; Agonist; Animal Model; Apical; Blood Pressure; Cells; Collaborations; Cyclic GMP; Data; Diet; Diuresis; Diuretics; Duct (organ) structure; Dynamin; Endocytosis; Endothelial Cells; Endothelin; Endothelin-1; Epithelial; Excretory function; Exhibits; Exons; Genetic; Human; Hypertension; In Vitro; Infusion procedures; Intake; Kidney; Knock-out; Knockout Mice; Laboratories; Lead; Mediator of activation protein; Molecular; Mus; NOS1 gene; Natriuresis; Nephrons; Nitrates; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Nitrites; Partner in relationship; Pathway interactions; Phenotype; Physiological; Population; Production; Protein Isoforms; RNA Splicing; Rattus; Receptor Activation; Reporting; Research; Role; Scheme; Sodium; Sodium Channel; Sodium Chloride; Source; Technology; Testing; Variant; Work; apical membrane; aquaporin-2; autocrine; epithelial Na+ channel; functional loss; in vivo; inhibitor/antagonist; kidney medulla; normotensive; novel; novel strategies; pressure; receptor; response; salt sensitive; saluretic; trafficking; young adult

We previously reported that sodium excretion is significantly correlated to the excretion of nitrate/nitrite (metabolites of nitric oxide) in normotensive young adults. This association of the nitric oxide pathway with sodium excretion in humans led us to probe the mechanisms of how this mediator acts in the physiological response to changes in sodium intake in animal models. It was previously shown that the inner medullary collecting duct has the highest nitric oxide synthase (NOS) activity in the rat kidney. All three NOS isoforms are expressed in the collecting duct. Loss of functional NOS1 through pharmacological inhibition in rats delays the excretion of sodium and blunts nitrite/nitrate excretion following an acute salt challenge. Since the final control of sodium excretion occurs in the collecting duct, we have recently created collecting duct specific NOS1 knockout (CD NOS1 KO) mice. These mice were generated by the cre-lox technology in which the floxed exon 6 NOS1 mouse was mated with the aquaporin 2-cre mouse resulting in a selective knockout of NOS1 in the renal collecting duct tubules. Our preliminary data indicates that the CD NOS1 KO mice are hypertensive when compared to the control mice. The first aim of this 2 year proposal is to test the hypothesis that the CD NOS1 KO mice will exhibit a salt-sensitive hypertensive phenotype. We also predict that the pressure-dependent natriuresis and diuresis is dysfunctional in the CD NOS1 KO mice when compared to the control mice. Several NOS1 splice variants are known to be expressed in the kidney. Our preliminary data demonstrates that NOS1b is the predominant splice variant expressed in the mouse medulla. Commercially available NOS1a knockout mice do not have any blood pressure anomaly, yet the CD NOS1 KO mice display a hypertensive phenotype and do not express any NOS1 variants. Thus, the second aim of this 2 year proposal is to test the hypothesis that the NOS1b splice variant contributes to the control of sodium reabsorption in the collecting duct.

我们先前报道说，钠排泄与正常的年轻人中硝酸盐/亚硝酸盐（一氧化氮的代谢产物）的排泄显着相关。一氧化氮途径与人类钠排泄的这种关联导致我们探究了该介体如何在动物模型中对钠摄入量变化的生理反应中的作用。以前显示，大鼠肾脏中内髓质收集导管具有最高的一氧化氮合酶（NOS）活性。所有三个NOS同工型均在收集管中表达。通过药理学抑制在大鼠中丧失了功能性NOS1，这延迟了急性盐挑战后钠和钝的亚硝酸盐/硝酸盐排泄的排泄。由于钠排泄的最终控制发生在收集管道中，因此我们最近创建了收集导管特定的NOS1敲除（CD NOS1 KO）小鼠。这些小鼠是由Cre-Lox技术产生的，其中Floxed Exon 6 NoS1小鼠与Aquaporin 2-Cre小鼠配对，从而在肾脏收集管小管中选择性敲除NOS1的选择性敲除。我们的初步数据表明，与对照小鼠相比，CD NOS1 KO小鼠是高血压。这两年提案的第一个目的是检验CD NOS1 KO小鼠将表现出盐敏感的高血压表型的假设。我们还预测，与对照小鼠相比，CD NOS1 KO小鼠的压力依赖性纳地尿和利尿作用在CD NOS1 KO小鼠中功能失调。已知在肾脏中表达了几种NOS1剪接变体。我们的初步数据表明，NOS1B是小鼠髓质中表达的主要剪接变体。市售的NOS1A基因敲除小鼠没有任何血压异常，但是CD NOS1 KO小鼠表现出高血压表型，并且没有表达任何NOS1变体。因此，这两年提案的第二个目的是检验以下假设：NOS1B剪接变体有助于控制收集管中的钠重吸收。

项目成果

Differential regulation of nitric oxide synthase function in aorta and tail artery from 5/6 nephrectomized rats.

• DOI: 10.1002/phy2.145
• 发表时间: 2013-11
• 期刊: PHYSIOLOGICAL REPORTS
• 影响因子: 2.5
• 作者: Spradley, Frank T;White, John J;Paulson, William D;Pollock, David M;Pollock, Jennifer S
• 通讯作者: Pollock, Jennifer S

Interaction between NO synthase and NADPH oxidase in control of sodium transport by the renal thick ascending limb during diabetes.

NO合酶和NADPH氧化酶之间的相互作用控制糖尿病期间肾厚升肢的钠转运。

• DOI: 10.1111/apha.12144
• 发表时间: 2013
• 期刊: Acta physiologica (Oxford, England)
• 作者: DeMiguel,C;Foster,JM;Carmines,PK;Pollock,JS
• 通讯作者: Pollock,JS

Gender differences in ET and NOS systems in ETB receptor-deficient rats: effect of a high salt diet.

ETB 受体缺陷大鼠 ET 和 NOS 系统的性别差异：高盐饮食的影响。

• DOI: 10.1161/01.hyp.0000048193.85814.78
• 发表时间: 2003
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Taylor,TraciA;Gariepy,CherylE;Pollock,DavidM;Pollock,JenniferS
• 通讯作者: Pollock,JenniferS

Renal NOS activity, expression, and localization in male and female spontaneously hypertensive rats.

• DOI: 10.1152/ajpregu.00526.2009
• 发表时间: 2010
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: J. Sullivan;Jennifer L. Pardieck;Kelly A. Hyndman;J. Pollock

Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1.

对比药理学 ETB 受体阻断与遗传性 ETB 缺陷对大 ET-1 的肾脏反应。

• DOI: 10.1152/physiolgenomics.2001.6.1.39
• 发表时间: 2001
• 期刊: Physiological genomics.
• 作者: Pollock,DM