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.

正常妊娠涉及广泛和系统的生理适应，其特征是大量的 体积扩张和血管舒张的生理变化的确切机制尚未完全阐明。 已澄清，但已发现松弛素（一种黄体释放激素）在控制 正常妊娠时的血流动力学变化可能会导致妊娠期间不适当或不充分的适应。 病理后果，例如先兆子痫，其特征是新发高血压和 妊娠 20 周后出现蛋白尿是先兆子痫期间肾脏血流动力学变化的特征。 与正常妊娠相比，GFR 和 RBF 降低约 20-40%。 合成（NOS）抑制不仅可以阻止正常妊娠期间 GFR 和 RBF 的升高，还可以抑制 GFR 和 RBF 的升高。 诱发高血压和蛋白尿，表明一氧化氮（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的血流动力学。 GFR 通常由肾小球反馈 (TGF) 反应调节 TGF 反应的重要性。 在正常妊娠和先兆子痫中TGF是否发生具体变化尚未阐明。 正常妊娠期间的反应是全身血管扩张的结果或原因 GFR 升高尚不清楚；先兆子痫期间 GFR 降低是否由 TGF 介导 引起高血压或高血压发展的结果的反应性尚不清楚；并且 致密斑中的 NOS1β 是否介导 TGF 改变并引发高血压的发生 所有这些未确定的领域都将在本提案中进行探讨。 我们将检验我们的假设，即正常妊娠期间致密斑中的 NOS1β 会增加，这 减弱 TGF 反应性，从而有助于维持 GFR 增加和血液减少 在先兆子痫期间，胎盘释放的因子会降低致密斑。 NOS1β 的表达和活性，可增强妊娠期间 GFR 的升高。 受到增强的 TGF 反应的限制，从而减少钠排泄，损害压力 排钠过多，从而诱发高血压。

项目成果

New mouse model of chronic kidney disease transitioned from ischemic acute kidney injury.

从缺血性急性肾损伤转变为慢性肾病的新小鼠模型。

• 发表时间: 2019-08-01
• 作者: Wei, Jin;Zhang, Jie;Wang, Lei;Jiang, Shan;Fu, Liying;Buggs, Jacentha;Liu, Ruisheng
• 通讯作者: Liu, Ruisheng

New Mechanism for the Sex Differences in Salt-Sensitive Hypertension: The Role of Macula Densa NOS1β-Mediated Tubuloglomerular Feedback.

盐敏感性高血压性别差异的新机制：致密斑 NOS1β 介导的肾小球反馈的作用。

• 发表时间: 2020
• 作者: Zhang, Jie;Zhu, Jinxiu;Wei, Jin;Jiang, Shan;Xu, Lan;Qu, Larry;Yang, Kun;Wang, Lei;Buggs, Jacentha;Cheng, Feng;Tan, Xuerui;Liu, Ruisheng
• 通讯作者: Liu, Ruisheng

Microvascular dysfunction and kidney disease: Challenges and opportunities?

微血管功能障碍和肾脏疾病：挑战和机遇？

• 发表时间: 2021-04
• 作者: Krishnan, Suraj;Suarez;Bagher, Pooneh;Gonzalez, Anjelica;Liu, Ruisheng;Murfee, Walter L;Mohandas, Rajesh
• 通讯作者: Mohandas, Rajesh

A new mechanism for the sex differences in angiotensin II-induced hypertension: the role of macula densa NOS1β-mediated tubuloglomerular feedback.

血管紧张素 II 诱发高血压性别差异的新机制：致密斑 NOS1β 介导的肾小管反馈的作用。

• 发表时间: 2020
• 作者: Zhang, Jie;Qu, Larry;Wei, Jin;Jiang, Shan;Xu, Lan;Wang, Lei;Cheng, Feng;Jiang, Kun;Buggs, Jacentha;Liu, Ruisheng
• 通讯作者: Liu, Ruisheng

Tubuloglomerular feedback: a key player in obesity-associated kidney injury.

肾小球反馈：肥胖相关肾损伤的关键因素。

• 发表时间: 2022-06-01
• 作者: Liu; Ruisheng
• 通讯作者: Ruisheng