Renal hemodynamics and hypertension during pregnancy

正常妊娠涉及广泛和系统的生理适应，其特点是 容量扩张和血管扩张。生理变化的确切机制还不完全清楚。 已阐明，但松弛素(一种黄体释放的激素)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和 妊娠20周后出现蛋白尿。先兆子痫患者肾脏血流动力学改变的特点 与正常妊娠相比，GFR和RBF减少了约20%-40%。非选择性一氧化氮 抑制合成(NOS)不仅阻止正常妊娠期间GFR和RBF的升高，而且还 导致高血压和蛋白尿，提示一氧化氮(NO)在控制高血压中的重要作用。 正常妊娠和子痫前期的血流动力学。 肾小球滤过率通常受肾小管小球反馈反应的调节。转化生长因子反应的意义 在正常妊娠和先兆子痫中的作用尚未阐明。具体来说，转化生长因子的变化是否 正常妊娠期间的反应是全身血管扩张的结果或导致 GFR增加尚不清楚；子痫前期GFR减少是否由转化生长因子介导 导致或导致高血压发展的反应尚不清楚；以及 致密斑内NOS1β是否参与转化生长因子的改变并触发高血压的发生 先兆子痫的病程尚不清楚。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，即致密黄斑中NOS1β在正常妊娠期间增加，这是 钝化有助于维持GFR增加和血液减少的转化生长因子的反应性 压力。在先兆子痫期间，从胎盘释放的因子会降低黄斑密度。 NOS1β的表达和活性增强了转化生长因子的反应性。妊娠期肾小球滤过率的升高 受到增强的转化生长因子反应的限制，转化生长因子反应减少钠的排泄，削弱压力 排钠，从而导致高血压。

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.