IMCD phosphodiesterase in pregnancy; role in ECFVE

妊娠期 IMCD 磷酸二酯酶；

• 批准号: 7229556
• 负责人: CHRISTINE BAYLIS
• 金额: $ 25.87万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-10 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229556
• 关键词: Acetylcholine; Acute; Agonist; Angiotensin II; Atrial Natriuretic Factor; Biological Assay; Blood Plasma Volume; Cells; Chronic; Cirrhosis; Companions; Controlled Study; Cyclic AMP; Cyclic GMP; Daily; Denervation; Dependence; Duct (organ) structure; Endocrine; Enzymes; Event; Extracellular Fluid; Failure; Goals; Guanylate Cyclase; Hormones; Hydrolysis; In Situ Hybridization; In Vitro; Kidney; Localized; Location; Measures; Mediating; Natriuresis; Nephrosis; Nerve; Northern Blotting; Outcome; Particulate; Patient currently pregnant; Peripheral Resistance; Phosphodiesterase Inhibitors; Physiological; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Progesterone; Prolactin; Prolactin-Releasing Hormone; Protein Isoforms; Proteins; Rattus; Relaxin; Role; Second Messenger Systems; Series; Signal Transduction; Sodium; Soluble Guanylate Cyclase; Staging; Stimulus; Supplementation; System; Techniques; Testing; Time; Tubular formation; Up-Regulation; Western Blotting; enzyme activity; fetal; hemodynamics; immunocytochemistry; in vivo; phosphodiesterase V; phosphoric diester hydrolase; pressure; prevent; research study; response; saluretic; second messenger

DESCRIPTION (provided by applicant): A large, sustained plasma volume expansion (PVE) is a necessary feature of normal, successful pregnancy. Suboptimal PVE is associated with adverse fetal outcome, and is a component of preeclampsia. The goal of this project is to determine the primary mechanism of the normal gestational PVE, so that ultimately, complications of pregnancy associated with failure to PVE can be prevented. This proposal is motivated by several marked similarities between the renal and hemodynamic responses to normal pregnancy, and those seen in states of inappropriate PVE, such as nephrosis or cirrhosis. The primary renal mechanism in pathological sodium retention is a failure of natriuretic mechanisms that rely on cGMP as second messenger, due to increased cGMP hydrolysis by phosphodiesterase (PDE). Here, we will test the hypothesis that selective upregulation of the renal tubular PDE system (particularly the inner medullary collecting duct, IMCD) occurs in pregnancy and causes widespread refractoriness to natriuretic stimuli, such as acute volume expansion and administered atrial natriuretic peptide, leading to PVE. We will also characterize the isoforms and location in the kidney of the PDEs involved in the renal response to normal P and determine whether increased renal PDE activity in pregnancy results from translational or posttranslational events. We will investigate how angiotensin II and renal nerve activity (major renal sodium retaining systems) are involved; we will test the "underfill" hypothesis of gestational PVE and we will determine whether the maternal hormones progesterone, prolactin or relaxin are primarily responsible for the increased renal PDE activity and PVE of P. Finally, we will chronically and locally inhibit the relevant PDE(s) during pregnancy to establish the impact on maternal hemodynamics and fetal outcome. All studies will be in rat, using a combination of in vivo techniques to measure renal sodium handling capacity and in vitro techniques on isolated glomeruli, proximal tubules and inner medullary collecting duct cells, to include enzyme activity assays, Western blot, immunocytochemistry, Northern blot or RNAse protection assay and in situ hybridization.

描述（由申请人提供）：大型的，持续的等离子体体积扩展（PVE）是正常，成功怀孕的必要特征。次级PVE与不良胎儿结局有关，并且是先兆子痫的组成部分。该项目的目的是确定正常妊娠PVE的主要机制，因此最终，可以防止与未能PVE相关的妊娠并发症。该提议是由肾脏和血液动力学对正常妊娠的几个明显相似性以及在不适当的PVE状态（例如肾脏病或肝硬化）中看到的几个明显相似之处。病理钠保留率的主要肾脏机制是由于磷酸二酯酶（PDE）的CGMP水解增加，依赖于CGMP作为第二信使的纳地尿机制的失败。在这里，我们将测试以下假设：肾小管PDE系统的选择性上调（尤其是内部髓质收集导管，IMCD）发生在妊娠中，并导致广泛的耐药性刺激性刺激性，例如急性体积膨胀，并施用了敏锐的Natriuretic Peptide。我们还将表征参与正常P肾脏反应的PDE肾脏中的同工型和位置，并确定妊娠中肾脏PDE活性增加是否来自翻译或翻译后事件导致。我们将研究血管紧张素II和肾神经活性（主要的肾脏钠保留系统）；我们将测试妊娠PVE的“下填充”假设，我们将确定母体激素孕激素，催乳素或松弛素主要负责肾脏PDE活性的增加和PVE。最后，我们将长期和局部在怀孕期间长期和局部抑制相关的PDE（S），以确定对母亲血液动力学的影响。 All studies will be in rat, using a combination of in vivo techniques to measure renal sodium handling capacity and in vitro techniques on isolated glomeruli, proximal tubules and inner medullary collecting duct cells, to include enzyme activity assays, Western blot, immunocytochemistry, Northern blot or RNAse protection assay and in situ hybridization.