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: 8886255
• 负责人: Allen W Cowley
• 金额: $ 39.49万
• 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/8886255
• 关键词: Affect; Aldosterone; Antioxidants; Beryllium; Blood Pressure; Blood flow; Cardiovascular Diseases; Chronic; Dahl Hypertensive Rats; Data; Development; Diabetes Mellitus; Diet; Diffuse; Diffusion; Distal; 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; Rectum; Regulation; 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; feeding; glomerular filtration; hypertension treatment; instrument; kidney cortex; 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（由适用提供）：肾脏调节钠和水调节在高血压中起关键作用，并且可以通过氧化应激途径显着损害。两个管状元素在建立Na+体内稳态方面至关重要，并且众所周知，两者都参与盐敏感形式的高血压，Henle（MTAL）的髓质较厚的升高（MTAL）和醛固酮敏感的远端Nephron（ASDN）。 SS大鼠的MTAL会产生过量的ROS，并且H2O2的清道夫慢性髓内输注量，可降低盐诱导的SS大鼠的高血压，几乎50％。相反，对正常大鼠H2O2的髓样输注可降低MBF和Na+极端，从而导致盐敏感的高血压形式。喂养高盐饮食的SS大鼠在ASDN段中还表现出更大的ENAC表达和活性，从而导致Na+的重吸收和盐诱导的高血压的增强。肾脏中ROS和H2O2的主要来源是NADPH氧化酶，但特定NOX同工型（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。肾脏中最丰富的同工型是NOX4，它的独特之处在于它主要释放出H2O2。然而，尚未进行研究以确定NOX4在Na+稳态和高血压中的作用。我们假设NOX4在SS大鼠的血压盐敏感性中起着主要作用，这两种方式：1）通过在Henle的肾外髓质厚的升高（MTAL）中过量产生H2O2，从而扩散了周围的Vasa Recta（VR）周围的phasa recta（VR），从而导致MBF的收集和重还原。 2）通过H2O2介导的ASDN中ENAC活性的增加。为了探索NOX4的作用，我们创建了一个新型的大鼠模型，其NOX4在SS大鼠中的空突变。我们将比较该突变大鼠SSNOX4 - / - 的响应与SS大鼠的四个具体目的：1-确定NOX4在SS大鼠（SSNOX4 - / - ）中对整个肾脏功能（MBF和GFR），肾脏氧化应激，肾脏氧化应激，压 - 含量，盐酸盐和Renate hyperte hyperte hyperts hyperts hyperte hyperts hyperts hyperts hyperts hypertss ss nox4的物理后果。 2-（新目标）确定SSNOX4 - / - 大鼠肾脏损伤的程度是较低的肾脏灌注压力与固有内部ROS产生的固有内部减少（肾脏灌注压力研究的伺服控制）的结果。 3确定性如果NOX4重要地参与了MTAL中的H2O2产生，以响应于腔内Na+的增加，以及H2O2是否可以从MTAL扩散到MTAL到周围的VR收缩。 4确定性如果在SS大鼠ASDN中产生H2O2和ENAC表达/活性是NOX4依赖性的。研究的设计是多尺度的，从细胞内到使用长期仪器大鼠的研究，这些大鼠在数周内监测MBF和GFR的变化。预计该结果将大大增强我们对NOX4在肾功能中的作用的理解，并导致靶向氧化应激途径在治疗高血压和肾脏疾病中的新方法。