Renal hemodynamics and hypertension during pregnancy

妊娠期肾脏血流动力学和高血压

• 批准号: 10090619
• 负责人: RUISHENG LIU
• 金额: $ 38.78万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090619
• 关键词: Acute; Address; Adenosine; Area; Blood Plasma Volume; Blood Pressure; Cardiac Output; Cells; Chronic; Data; Development; Dilatation - action; Etiology; Excretory function; Feedback; Generations; Glomerular Filtration Rate; Hormones; Hypertension; Impairment; Ischemia; Kidney; Macula densa; Measures; Mediating; Modeling; Mus; NOS1 gene; Natriuresis; Neonatal Mortality; Nephrons; Neurons; Nitric Oxide; Pathologic; Perfusion; Peripheral Resistance; Physiological; Physiological Adaptation; Placenta; Plasma; Play; Pre-Eclampsia; Pregnancy; Prevention; Process; Proteinuria; RNA Splicing; Regulation; Relaxin; Renal Blood Flow; Role; Sodium; Telemetry; Testing; Tubular formation; Uterus; Variant; Vasodilation; Water; Wild Type Mouse; arteriole; corpus luteum; fetal; hemodynamics; neonatal morbidity; novel; pregnant; pressure; release factor; response; therapeutic target

Normal pregnancy involves extensive and systemic physiological adaptations characterized by substantial volume expansion and vasodilatation. The exact mechanisms for the physiological changes have not been fully clarified, but relaxin (a corpus luteum-released hormone) has been found to play a central role in the control of hemodynamics in normal pregnancy. Inappropriate or inadequate adaptations during pregnancy may induce pathological consequences such as preeclampsia, which is characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. Renal hemodynamic alterations during preeclampsia are characterized by reduced GFR and RBF by about 20-40% compared with normal pregnancies. Non-selective nitric oxide synthesis (NOS) inhibition not only blocks the elevations in GFR and RBF during normal pregnancy, but also induces hypertension and proteinuria, suggesting the essential role of nitric oxide (NO) in control of the hemodynamics in normal pregnancy and preeclampsia. GFR is normally regulated by tubuloglomerular feedback (TGF) response. The significance of TGF response in normal pregnancy and preeclampsia has not been elucidated. Specifically, whether the changes in TGF response during normal pregnancy are a consequence of systemic vessel dilatation or the cause for the increased GFR is unknown; whether the decreased GFR during preeclampsia is mediated by TGF responsiveness, which induces or is a consequence of the development of hypertension is unknown; and whether NOS1β in the macula densa mediates TGF alterations and triggers the development of hypertension during preeclampsia is unknown. All of these unidentified areas will be explored in the present proposal. We will test our hypothesis that NOS1β in the macula densa increases during normal pregnancy, which blunts TGF responsiveness that contributes to maintaining increased GFR and decreased blood pressure. During preeclampsia, factors that are released from the placenta decrease the macula densa NOS1β expression and activity, which enhances TGF responsiveness. Elevations of GFR in pregnancy are limited by the enhanced TGF response, which reduces sodium excretion, impairs pressure natriuresis, and thereby induces hypertension.

正常妊娠涉及广泛的和系统的生理适应，其特征在于大量的 体积膨胀和血管舒张。生理变化的确切机制尚未完全阐明 澄清，但松弛素（黄体释放激素）已被发现在控制 正常妊娠的血流动力学。怀孕期间不适当或不充分的适应可能会导致 病理后果，如先兆子痫，其特征是新发高血压， 妊娠20周后出现蛋白尿。先兆子痫时肾血流动力学改变的特点是 与正常妊娠相比，GFR和RBF降低约20-40%。非选择性氧化氮 一氧化氮合酶（NOS）抑制不仅可以阻断正常妊娠期间GFR和RBF的升高， 诱导高血压和蛋白尿，提示一氧化氮（NO）在控制高血压和蛋白尿中的重要作用。 正常妊娠和先兆子痫血流动力学研究 GFR通常由肾小管肾小球反馈（TGF）反应调节。TGF反应的意义 在正常妊娠和先兆子痫中的作用尚未阐明。具体来说，TGF的变化是否 正常妊娠期间的反应是全身血管扩张的结果或导致 尚不清楚GFR升高;先兆子痫期间GFR降低是否由TGF-β 1介导 引起高血压或高血压发展的结果的反应性尚不清楚;以及 致密斑中的NOS 1 β是否介导TGF改变并触发高血压的发展 先兆子痫的发病率是未知的。本提案将探讨所有这些未确定的领域。 我们将检验我们的假设，即在正常妊娠期间致密斑中NOS 1 β增加， 减弱TGF反应性，有助于维持GFR增加和血流量减少 压力在先兆子痫期间，从胎盘释放的因子减少了致密斑， NOS 1 β表达和活性增强TGF反应性。妊娠期GFR升高 受到增强的TGF反应的限制，这减少了钠排泄，损害了压力， 尿钠排泄，从而诱发高血压。

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