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风险增加相关。我们的实验室开发了一种独特的大鼠胎盘功能不全模型，该模型会导致雄性 IUGR 出现与高血压相关的宫内生长受限 (IUGR)，但雌性 IUGR 则不会。重要的是，去势可以消除 IUGR 男性的高血压。卵巢切除术 (OVX) 会导致 IUGR 女性血压 (BP) 显着升高。因此，性激素可能介导成人 IUGR 血压的差异；然而，确切的机制仍然未知。初步数据表明，男性 IUGR 的肾内皮素 (ET) 增加，女性 IUGR 的肾内皮素 (ET) 因 OVX 的反应而增加；选择性 ETA 受体阻断可消除男性 IUGR 和 OVX 女性 IUGR 中的高血压。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。使用 tempol（一种 SOD 模拟物）进行长期治疗，可消除男性 IUGR 和女性 OVX IUGR 中增加的氧化应激和高血压。我们报告称，肾素血管紧张素系统（RAS）在高血压 IUGR 中发挥着关键作用；然而，外周和肾内 RAS 水平并未升高。 ET 可增加对血管紧张素 II (ANG II) 的反应性；初步数据表明，男性 IUGR 和 OVX 女性 IUGR 对 ANG II 的反应性有所增加。因此，ET 诱导的氧化应激和血管对 ANG II 的反应可能是 ET 导致 IUGR BP 性别差异的可能机制。因此，我们假设睾酮通过增强内皮素系统来增加肾血管阻力并加剧男性 IUGR 的高血压，从而导致氧化应激和血管对血管紧张素 II 的反应性增加；雌二醇通过削弱内皮素系统来降低女性 IUGR 的肾血管阻力和血压，从而防止氧化应激和血管对血管紧张素 II 的反应性增加。我们将测试以下具体目标： 具体目标1：睾酮通过增强内皮素系统进一步增加肾血管阻力并加剧男性IUGR的高血压；雌二醇通过减弱内皮素系统来降低 IUGR 女性的肾血管阻力和血压。具体目标2：睾酮介导的内皮素生成增加会增加氧化应激，导致肾血管阻力进一步增加，并加剧男性IUGR的高血压；雌二醇介导的内皮素产生减弱可减少氧化应激，从而降低 IUGR 女性的肾血管阻力和血压。具体目标 3：睾酮介导的内皮素生成增强，增加血管对血管紧张素 II 的反应性，进一步增加肾血管阻力，加剧男性 IUGR 的高血压；雌二醇介导的内皮素产生减弱会降低血管对血管紧张素 II 的反应性，从而导致 IUGR 女性肾血管阻力和血压降低。公共健康相关性：有令人信服的流行病学和实验数据表明，高血压等心血管疾病可能是在子宫内形成的。我们的实验室利用一种独特的低出生体重模型来模拟人类胎儿生长缓慢（与心血管疾病风险增加相关）的情况，以研究出生体重与高血压之间的联系机制。因此，我们的研究结果可能意味着低出生体重个体的医疗保健中的预防性干预措施可能会阻止心血管疾病和高血压的发生。