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.

我们之前报道过，在血压正常的年轻人中，钠排泄与硝酸盐/亚硝酸盐（一氧化氮的代谢物）的排泄显着相关。一氧化氮途径与人类钠排泄的这种关联促使我们探索这种介质如何在动物模型中对钠摄入量变化的生理反应中发挥作用的机制。先前的研究表明，大鼠肾脏内髓集合管的一氧化氮合酶（NOS）活性最高。所有三种 NOS 亚型均在集合管中表达。大鼠因药物抑制而丧失功能性 NOS1 会延迟钠的排泄，并在急性盐挑战后减弱亚硝酸盐/硝酸盐的排泄。由于钠排泄的最终控制发生在集合管中，我们最近创建了集合管特异性 NOS1 敲除（CD NOS1 KO）小鼠。这些小鼠是通过 cre-lox 技术产生的，其中 floxed 外显子 6 NOS1 小鼠与水通道蛋白 2-cre 小鼠交配，导致肾集合管中 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 小鼠患有高血压。这个为期两年的提案的首要目的是检验 CD NOS1 KO 小鼠将表现出盐敏感性高血压表型的假设。我们还预测，与对照小鼠相比，CD NOS1 KO 小鼠的压力依赖性尿钠排泄和利尿功能失调。已知多种 NOS1 剪接变体在肾脏中表达。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 敲除小鼠没有任何血压异常，但 CD NOS1 KO 小鼠表现出高血压表型，并且不表达任何 NOS1 变异体。因此，这个为期两年的提案的第二个目标是检验 NOS1b 剪接变体有助于控制集合管中钠重吸收的假设。

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

Protective role of extracellular superoxide dismutase in renal ischemia/reperfusion injury.

• DOI: 10.1038/ki.2010.141
• 发表时间: 2010-08
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Schneider, Markus P.;Sullivan, Jennifer C.;Wach, Paul F.;Boesen, Erika I.;Yamamoto, Tatsuo;Fukai, Tohru;Harrison, David G.;Pollock, David M.;Pollock, Jennifer S.
• 通讯作者: Pollock, Jennifer S.

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