Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension

NOX4 在盐敏感性高血压肾功能中的作用

• 批准号: 9444474
• 负责人: Allen W Cowley
• 金额: $ 38.38万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444474
• 关键词: Affect; Aldosterone; Antioxidants; Blood Pressure; Blood flow; Cardiovascular Diseases; Chronic; Dahl Hypertensive Rats; Data; Development; Diabetes Mellitus; Diffuse; Diffusion; Distal; Elements; Ensure; Environment; Enzymes; Excretory function; Exhibits; Free Radical Scavenging; Functional disorder; Generations; Grant; Homeostasis; Hydrogen Peroxide; Hypertension; Infusion procedures; Injury; Intake; Kidney; Kidney Diseases; Knock-out; Laboratories; Lead; Limb structure; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; NADP; NADPH Oxidase; Natriuresis; Nephrons; Nitric Oxide; Oral; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Patients; Perfusion; Pericytes; Physiological; Play; Production; Protein Isoforms; Publishing; Rattus; Reactive Oxygen Species; Regulation; Renal Blood Flow; Renal function; Reporting; Research; Resistance; Role; Signal Transduction; Sodium; Sodium Chloride; Source; Therapeutic; Thick; Tubular formation; Water; Wisconsin; antioxidant therapy; blood pressure regulation; catalase; constriction; design; epithelial Na+ channel; glomerular filtration; high salt diet; hypertension treatment; instrument; kidney cortex; kidney interstitial tissue; kidney medulla; medical schools; mutant; novel; null mutation; pressure; public health relevance; response; salt sensitive; salt sensitive hypertension

 DESCRIPTION (provided by applicant): Sodium and water regulation by the kidney plays a key role in hypertension and can be significantly compromised by pathways of oxidative stress. Two tubular elements are of major importance in establishing Na+ homeostasis and both are known to participate in salt-sensitive forms of hypertension, the medullary thick ascending limb of Henle (mTAL) and the aldosterone sensitive distal nephron (ASDN). The mTAL of SS rats produces excess ROS and the chronic intramedullary infusion of catalase, a scavenger of H2O2, reduces salt- induced hypertension nearly 50% in SS rats. Conversely, medullary infusion of H2O2 to normal rats reduces MBF and Na+ excretion resulting in a salt-sensitive form of hypertension. SS rats fed a high salt diet also exhibit greater expression and activity of ENaC in the ASDN segments leading to greater reabsorption of Na+ and enhancement of salt-induced hypertension. The major source of ROS and H2O2 in the kidney is NADPH oxidase but the roles of specific Nox isoforms such as Noxs 1, 2 and 4 and the mechanisms whereby they affect renal function have not been well elucidated. The most abundant isoform in the kidney is Nox4 which is unique in that it releases predominantly H2O2. Yet no studies have been carried out to determine the role of Nox4 in Na+ homeostasis and hypertension. We hypothesize that Nox4 plays a dominant role in determining blood pressure salt-sensitivity in the SS rat in two ways: 1) By excess production of H2O2 in the renal outer medullary thick ascending limbs of Henle (mTAL) which diffuses to surrounding vasa recta (VR) pericytes causing constriction and reduction of MBF; 2) Through H2O2-mediated increases of ENaC activity in the ASDN. To explore the role of Nox4, we have created a novel rat model with a null mutation of Nox4 in the SS rat. We will compare the responses of this mutant rat, SSNox4-/-, to those of the SS rat in four Specific Aims: 1- Determine physiological consequences of a null mutation of Nox4 in SS rats (SSNox4-/-) upon whole kidney function (MBF and GFR), renal oxidative stress, pressure-natriuresis, salt-induced hypertension and renal injury. 2-(New Aim) Determine the extent to which the reduced renal injury in SSNox4-/- rats is a consequence of a lower renal perfusion pressure versus an inherent intrarenal reduction of ROS production (servo-control of renal perfusion pressure studies). 3-Determine if Nox4 is importantly involved in H2O2 production in mTAL in response to increased luminal Na+ delivery and whether H2O2 can diffuse from mTAL to constrict surrounding VR. 4-Determine if production of H2O2 and ENaC expression/activity in ASDN of SS rats is Nox4-dependent. Studies are multiscale in design ranging from intracellular to those utilizing chronically instrumented rats which monitor changes in MBF and GFR over several weeks. The results are expected to greatly enhance our understanding of the role of Nox4 in renal function and lead to novel ways to target pathways of oxidative stress in the treatment of hypertension and renal disease.

 描述（由申请人提供）：肾脏对钠和水的调节在高血压中起着关键作用，并且可能会受到氧化应激途径的显着损害。两个管状元件对于建立 Na+ 稳态至关重要，并且已知两者都参与盐 - SS 大鼠的髓质厚升支 (mTAL) 和醛固酮敏感远端肾单位 (ASDN) 会产生过量的 ROS 和高血压的敏感形式。长期髓内输注过氧化氢酶（H2O2 的清除剂）可将 SS 大鼠的盐诱发高血压降低近 50%，向正常大鼠髓内输注 H2O2 可减少 MBF 和 Na+ 排泄，从而导致 SS 大鼠出现盐敏感型高血压。高盐饮食还会在 ASDN 节段中表现出更高的 ENaC 表达和活性，从而导致更多的 Na+ 重吸收并增强盐诱导的高血压。 ROS 和 ROS 的主要来源。肾脏中的 H2O2 是 NADPH 氧化酶，但特定 Nox 异构体（例如 Noxs 1、2 和 4）的作用以及它们影响肾功能的机制尚未得到很好的阐明。肾脏中最丰富的异构体是 Nox4，其独特之处在于。它主要释放 H2O2，但尚未进行任何研究来确定 Nox4 在 Na+ 稳态和高血压中的作用。通过两种方式确定 SS 大鼠的血压盐敏感性：1) 通过肾外髓厚升肢 Henle (mTAL) 产生过量的 H2O2，其扩散到周围直肠血管 (VR) 周细胞，导致收缩和 MBF 减少; 2) 通过 H2O2 介导的 ASDN 中 ENaC 活性的增加 为了探索 Nox4 的作用，我们创建了一种具有 无效突变的新型大鼠模型。 SS 大鼠中的 Nox4 我们将在四个具体目标中比较这种突变大鼠 SSNox4-/- 与 SS 大鼠的反应： 1- 确定 SS 大鼠中 Nox4 无效突变 (SSNox4-/) 的生理后果。 -) 根据整个肾功能（MBF 和 GFR）、肾氧化应激、压力尿钠、盐诱发的高血压和肾损伤 2-（新目标）确定减少的程度。 SSNox4-/- 大鼠的肾损伤是肾灌注压降低与肾内 ROS 产生固有减少的结果（肾灌注压研究的伺服控制） 3-确定 Nox4 是否显着参与 mTAL 中 H2O2 的产生。对增加的管腔 Na+ 输送的反应以及 H2O2 是否可以从 mTAL 扩散以收缩周围的 VR 4-确定 SS 的 ASDN 中是否产生 H2O2 和 ENaC 表达/活性。研究采用多尺度设计，从细胞内到长期监测大鼠的 MBF 和 GFR 数周的变化，预计结果将大大增强我们对 Nox4 在肾功能中的作用的理解。治疗高血压和肾脏疾病中针对氧化应激途径的新方法。