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.