Low birth weight, the kidney, 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有关。我们实验室建立了一种独特的大鼠胎盘功能不全模型，这种模型导致雄性IUGR合并高血压的宫内生长受限(IUGR)，但在雌性IUGR中没有。重要的是，去势消除了男性IUGR的高血压；卵巢切除(OVX)导致女性IUGR的血压(BP)显著升高。因此，性激素可能会调节成人IUGR BP的差异；然而，确切的机制(S)仍不清楚。初步数据表明，男性IUGR的肾脏内皮素(ET)升高，女性IUGR对OVX的反应增强，选择性ETA受体阻滞剂可消除男性IUGR和OVX女性IUGR的高血压。因此，性激素对ET的调节可能是IUGR BP性别差异的关键。初步数据显示，男性IUGR和OVX女性IUGR的氧化应激增加。用一种类似超氧化物歧化酶的药物坦普尔进行慢性治疗，可以消除男性IUGR和女性OVX IUGR中增加的氧化应激和高血压。我们报告肾素血管紧张素系统(RAS)在高血压IUGR中起关键作用；然而，RAS的外周和肾内水平并不升高。ET可增加对血管紧张素II(Ang II)的反应性；初步数据显示，男性IUGR和OVX女性IUGR对Ang II的反应性增强。因此，ET诱导的氧化应激和血管对Ang II的反应性可能是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，增加男性IUGR的肾血管阻力，加重高血压，从而导致氧化应激和血管对血管紧张素II的反应性增加；雌二醇通过减弱内皮素系统，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：特定目标1：睾酮通过增强内皮素系统，进一步增加男性IUGR的肾血管阻力，加剧高血压；雌二醇通过减弱内皮素系统，降低女性IUGR的肾血管阻力和血压。具体目的2：睾酮介导的内皮素生成增加增加氧化应激，导致男性IUGR肾血管阻力进一步增加，加重高血压；雌二醇介导的内皮素生成减少，氧化应激降低，导致女性IUGR肾血管阻力和血压下降。具体目的3：睾酮介导的内皮素生成增加了血管对血管紧张素II的反应性，进一步增加了男性IUGR的肾血管阻力，加重了高血压；雌二醇介导的内皮素产生的减少降低了血管对血管紧张素II的反应性，导致女性IUGR的肾血管阻力和血压下降。公共卫生相关性：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编程的。我们的实验室利用一种独特的低出生体重大鼠模型，模拟与心血管疾病风险增加相关的胎儿生长缓慢的人类状况，以研究出生体重和高血压之间的联系机制。因此，我们的研究结果可能暗示在低出生体重者的健康护理中进行预防性干预，这可能会阻止心血管疾病和高血压的发生。

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.