Low birth weight, the kidney, and hypertension

低出生体重、肾脏和高血压

• 批准号: 7843157
• 负责人: Barbara T Alexander
• 金额: $ 1.43万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843157
• 关键词: ANG gene; Acute; Address; Adult; Angiotensin II; Animal Model; Attenuated; Birth Weight; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Castration; Chronic; Data; Development; Endothelin; Epidemiology; Estradiol; Excretory function; Exhibits; Female; Fetal Growth; Fetal Growth Retardation; Funding; Gonadal Steroid Hormones; Healthcare; Human; Hypertension; Individual; Intervention; Kidney; Laboratories; Link; Low Birth Weight Infant; Mediating; Messenger RNA; Modeling; Molecular; Ovariectomy; Oxidative Stress; Peripheral; Physiological; Placental Insufficiency; Play; Production; Proteins; Puberty; Rattus; Renal Blood Flow; Renin-Angiotensin System; Reporting; Role; Sex Characteristics; Stress; System; Techniques; Testing; Testosterone; Vascular resistance; attenuation; base; cardiovascular disorder risk; in utero; kidney vascular structure; male; mimetics; novel; offspring; prevent; programs; public health relevance; receptor; response; tempol; urinary

DESCRIPTION (provided by applicant): Low birth weight is associated with an increased risk for cardiovascular disease. Our laboratory has developed a unique model of placental insufficiency in the rat that results in intrauterine growth restriction (IUGR) associated with hypertension in male IUGR, but not in female IUGR. Importantly, castration abolishes hypertension in male IUGR; ovariectomy (OVX) induces a marked increase in blood pressure (BP) in female IUGR. Thus, sex hormones may mediate differences in adult IUGR BP; yet, the exact mechanism(s) remains unknown. Preliminary data suggest that renal endothelin (ET) is increased in male IUGR and in response to OVX in female IUGR; hypertension in male IUGR and OVX female IUGR is abolished by selective ETA receptor blockade. Therefore, modulation of ET by sex hormones may be critical to sex differences in IUGR BP. Preliminary data suggest oxidative stress is increased in male IUGR and OVX female IUGR. Chronic treatment with tempol, a SOD mimetic, abolishes increased oxidative stress and hypertension in male IUGR and female OVX IUGR. We report that the renin angiotensin system (RAS) plays a critical role in hypertensive IUGR; however, peripheral and intrarenal levels of the RAS are not elevated. ET can increase responsiveness to angiotensin II (ANG II); preliminary data suggest responsiveness to ANG II is increased in male IUGR and OVX female IUGR. Thus, ET induced oxidative stress and vascular responsiveness to ANG II may serve as possible mechanisms by which ET contributes to sex differences in IUGR BP. Thus, we hypothesize that testosterone increases renal vascular resistance and exacerbates hypertension in male IUGR by enhancing the endothelin system, thus leading to increased oxidative stress and vascular responsiveness to angiotensin II; and that estradiol decreases renal vascular resistance and blood pressure in female IUGR by attenuating the endothelin system, thus preventing an increase in oxidative stress and vascular responsiveness to angiotensin II. We will test the following specific aims: Specific aim 1: That testosterone further increases renal vascular resistance and exacerbates hypertension in male IUGR by enhancing the endothelin system; and that estradiol reduces renal vascular resistance and blood pressure in female IUGR by attenuating the endothelin system. Specific aim 2: That testosterone-mediated enhanced endothelin production increases oxidative stress leading to a further increase in renal vascular resistance and exacerbating hypertension in male IUGR; and that estradiol-mediated attenuation of endothelin production decreases oxidative stress leading to a reduction in renal vascular resistance and blood pressure in female IUGR. Specific aim 3: That testosterone-mediated enhanced endothelin production increases vascular responsiveness to angiotensin II further increasing renal vascular resistance and exacerbating hypertension in male IUGR; and that estradiol- mediated attenuation of endothelin production decreases the vascular responsiveness to angiotensin II leading to a reduction in renal vascular resistance and blood pressure in female IUGR. PUBLIC HEALTH RELEVANCE: There is compelling epidemiological and experimental data which suggest that cardiovascular diseases such as hypertension may be programmed in-utero. Our laboratory utilizes a unique model of low birth weight in that rat that mimics the human condition of slow fetal growth associated with an increased risk for cardiovascular disease to investigate the mechanisms linking the birth weight and hypertension. Thus, findings from our studies may implicate preventative interventions in the health care of low birth weight individuals that may preclude the development of cardiovascular disease and hypertension.

描述（由申请人提供）：低出生体重与心血管疾病的风险增加有关。我们的实验室已经开发了大鼠胎盘不足的独特模型，从而导致与雄性IUGR高血压相关的宫内生长限制（IUGR），但在雌性IUGR中却不相关。重要的是，cast割废除了男性IUGR的高血压；卵巢切除术（OVX）诱导女性IUGR的血压显着增加（BP）。因此，性激素可能介导成人IUGR BP的差异。然而，确切的机制仍然未知。初步数据表明，雄性IUGR的肾脏内皮素（ET）增加，而女性IUGR的OVX响应；雄性IUGR和OVX雌性IUGR的高血压被选择性ETA受体阻滞剂废除。因此，性激素对ET的调节可能对IUGR BP的性别差异至关重要。初步数据表明，男性IUGR和OVX女性IUGR的氧化应激增加。用tempol的慢性治疗，一种模拟物，废除雄性IUGR和雌性OVX IUGR的氧化应激和高血压的增加。我们报告说，肾素血管紧张素系统（RAS）在高血压IUGR中起着至关重要的作用。但是，RAS的外周和内部水平尚未升高。 ET可以提高对血管紧张素II的反应性（ANG II）；初步数据表明，男性IUGR和OVX女性IUGR对ANG II的反应性有所提高。因此，ET诱导的氧化应激和对ANG II的血管反应能力可以作为可能的机制，ET会导致IUGR BP的性别差异。因此，我们假设睾丸激素通过增强内皮素系统增加了雄性IUGR的肾血管抗性，并加剧了雄性IUGR的高血压，从而导致氧化应激和对血管紧张素II的血管反应增加。雌二醇通过减轻内皮素系统来降低雌性IUGR的肾血管耐药性和血压，从而防止氧化应激和血管素II的血管反应性增加。我们将测试以下特定目的：特定目标1：睾丸激素进一步增加了肾血管抗性，并通过增强内皮素系统来加剧男性IUGR的高血压；雌二醇通过减轻内皮素系统来降低雌性IUGR的肾血管耐药性和血压。具体目标2：睾丸激素介导的增强的内皮素产生增加了氧化应激，从而导致雄性IUGR的肾血管耐药性进一步增加和加剧的高血压。雌二醇介导的内皮素产生的衰减会降低氧化应激，从而降低雌性IUGR肾血管耐药性和血压。具体目标3：睾丸激素介导的增强的内皮素产生增加了对血管紧张素II的血管反应性进一步增加了雄性IUGR的肾血管抗性和加剧的高血压。雌二醇介导的内皮素产生的衰减降低了对血管紧张素II的血管反应性，从而导致雌性IUGR的肾血管耐药性和血压降低。公共卫生相关性：有令人信服的流行病学和实验数据表明，可以在UTERO中对心血管疾病（例如高血压）进行编程。我们的实验室利用了低出生体重的独特模型，其中模仿了与心血管疾病的风险增加相关的人类缓慢生长状况，以研究将出生体重和高血压联系起来的机制。因此，我们研究的发现可能暗示了低出生体重个体的医疗保健中的预防干预措施，这可能排除心血管疾病和高血压的发展。