The Impact of Antenatal Steroid Exposure on the Intrarenal Renin-Angiotensin

产前类固醇暴露对肾内肾素-血管紧张素的影响

• 批准号: 8918005
• 负责人: JAMES C. ROSE
• 金额: $ 17.27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918005
• 关键词: Adult; Adverse event; Age; Angiotensin II; Angiotensin II Receptor; Angiotensins; Animals; Betamethasone; Binding; Biological Assay; Birth; Blood Pressure; Cell membrane; Cells; Child; Data; Deterioration; Development; Discipline of obstetrics; Disease; Dose; Early Intervention; Equilibrium; Event; Excretory function; Exposure to; Fetal Lung; Funding; Gender; Glucocorticoids; Human; Hyperphagia; Hypertension; In Vitro; Injury; Instruction; Kidney; Kidney Diseases; Knowledge; Lead; Literature; Measures; Mediator of activation protein; Monitor; Natriuresis; Nephrectomy; Nephrons; Nuclear Envelope; Obesity; Outcome; Peptide Receptor; Peptides; Population; Population Intervention; Predisposition; Pregnancy; Pregnant Women; Production; Receptor Signaling; Renal Hypertension; Renal Tissue; Renal function; Renin; Renin-Angiotensin System; Reporting; Resources; Risk; Risk Factors; Sheep; Signal Pathway; Sodium; Sodium Chloride; Specificity; Staging; Steroids; Testing; Time; Tubular formation; Type 2 Angiotensin II Receptor; base; clinically relevant; enzyme activity; high risk; interest; loss of function; modifiable risk; nephrogenesis; offspring; postnatal; premature; prenatal; prenatal exposure; prenatal influence; prevent; programs; receptor; response; saluretic; theories

Substantial evidence demonstrates that prenatal events have effects on development resulting in pathophysiological consequences in adulthood. The outcome of some of these effects is a predisposition to certain diseases including hypertension. Our data from the previous funding period demonstrate that prenatal exposure to clinically relevant doses of glucocorticoids at a critical stage of gestation (peak of nephrogenesis) reduces nephron number, impairs excretion of a salt load (that is gender dependent) and elevates blood pressure in adulthood. Although knowledge of the mechanisms whereby sodium excretion is altered is nearly nonexistent, alterations in the intrarenal renin-angiotensin system (RAS) which we have reported may be involved. In addition, it is not known if the alterations in renal development and the intrarenal RAS result in greater susceptibility to renal damage and greater loss of function following a second insult. Therefore this proposed project has two objectives. The first is to determine if the mechanisms responsible for the reduced ability to excrete a sodium load involve alterations in the receptors/signaling pathways that respond to the angiotensin peptides in the kidney. The second is to ascertain if prenatal betamethasone exposure results in higher risk for additional renal damage from an adverse event after birth. We will study sheep, because they are similar to humans in terms of the timing of nephrogenesis relative to stage of gestation and because these animals provide sufficient quantities of renal tissue for our in vitro studies. We hypothesize that: 1) the mechanisms involved in the reduced ability to excrete a sodium load include reductions in the ability of Ang peptides to activate signaling pathways associated with natriuresis; and, 2) prenatal betamethasone exposure results in greater risk for renal damage and reductions in function following a second insult afterbirth. We will use specific assays to measure the angiotensin peptides and key components in the signaling pathways activated by them associated with natriuresis. Binding assays will be used to assess receptors for these peptides. We will use unilateral nephrectomy or obesity (induced by voluntary overeating) as second "hits" and evaluate renal function and markers of renal damage to establish if there is a predisposing relationship between prenatal betamethasone and subsequent renal injury. Understanding more about the impact of antenatal glucocorticoids on renal function and susceptibility to renal damage in adulthood is important because of the widespread use of glucocorticoids in Obstetrics today. Our studies may identify a population at greater risk for renal disease and hypertension as they mature which could result in approaches for monitoring this at risk population and early intervention to prevent premature deterioration of renal function in adulthood.

大量证据表明，产前事件对发展产生了影响，从而在成年期间导致病理生理后果。其中一些影响的结果是对包括高血压在内的某些疾病的倾向。我们上一个资金期的数据表明，在妊娠的关键阶段（肾脏发生的峰值）在临床上相关剂量的糖皮质激素接触会减少肾单位数，从而损害盐负荷的排泄（这是性别依赖性）并升高了血压的血压。尽管对钠排泄改变的机制的了解几乎不存在，但可能涉及我们报告的肾内肾素 - 血管紧张素系统（RAS）的改变。此外，尚不清楚肾脏发育和肾内RAS的改变是否会导致更大的敏感性对肾脏损伤和第二次侮辱后更大的功能丧失。因此，该提议的项目有两个目标。首先是确定负责排泄钠负荷能力的机制是否涉及对肾脏中血管紧张素肽反应的受体/信号通路的改变。第二个是确定产前倍他米松的暴露是否会导致出生后发生不良事件的肾脏损害的风险更高。我们将研究绵羊，因为它们与人类相似，就肾脏的时间而言，相对于妊娠期的时间，这些动物为我们的体外研究提供了足够数量的肾脏组织。我们假设：1）排泄钠载荷能力降低的机制包括降低ANG肽激活与Natriuresis相关的信号通路的能力； 2）产前倍替塞米松的暴露会导致肾脏损伤的风险更大，并在第二次侮辱后功能降低。我们将使用特定的测定法来测量与纳地那氏菌相关的信号传导途径中的血管紧张素肽和关键成分。结合测定将用于评估这些肽的受体。我们将使用单侧肾切除术或肥胖症（由自愿暴饮暴食引起）作为第二个“命中”，并评估肾功能和肾脏损害的标志物，以确定产前β可塞松和随后的肾脏损伤之间是否存在易感性关系。更多地了解产前糖皮质激素对成年后肾功能的影响和对肾脏损害的易感性，这一点很重要，因为当今的产科中，糖皮质激素广泛使用。我们的研究可能会发现肾脏疾病和高血压风险更大的人群，因为它们成熟，这可能会导致在风险人群和早期干预中监测该肾脏的方法，以防止成年后肾功能过早恶化。