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，产前事件对发育产生影响，导致成年后的病理生理后果。其中一些影响的结果是易患某些疾病，包括高血压。我们从上一个资助期的数据表明，产前暴露于临床相关剂量的糖皮质激素在妊娠的关键阶段（肾发生高峰期）减少肾单位数量，损害排泄的盐负荷（这是性别依赖），并提高血压在成年期。虽然钠排泄改变的机制的知识几乎是不存在的，在肾内的肾素-血管紧张素系统（RAS），我们已经报告的改变可能涉及。此外，尚不清楚肾脏发育和肾内RAS的改变是否会导致对肾损伤的更大易感性和二次损伤后更大的功能丧失。因此，拟议的项目有两个目标。第一个是确定负责排泄钠负荷能力降低的机制是否涉及对肾脏中的血管紧张素肽做出响应的受体/信号传导途径的改变。第二个是确定产前暴露是否会导致出生后不良事件导致额外肾损伤的风险更高。我们将研究绵羊，因为它们在相对于妊娠阶段的肾发生时间方面与人类相似，并且因为这些动物为我们的体外研究提供了足够数量的肾组织。我们假设：1）排泄钠负荷的能力降低的机制包括Ang肽激活与尿钠排泄相关的信号通路的能力降低;和2）产前暴露于β-肾上腺素导致肾损伤的更大风险和第二次损伤后的功能降低。我们将使用特定的测定来测量血管紧张素肽和由它们激活的与尿钠排泄相关的信号通路中的关键组分。结合试验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（由自愿暴饮暴食引起）作为第二次“打击”，并评估肾功能和肾损伤的标志物，以确定产前肥胖和随后的肾损伤之间是否存在易感关系。了解更多关于产前糖皮质激素对肾功能的影响和成年后对肾损害的易感性是重要的，因为糖皮质激素在产科的广泛使用。我们的研究可能会确定一个人群在肾脏疾病和高血压的风险更大，因为他们的成熟，这可能会导致监测这种风险人群和早期干预的方法，以防止肾功能在成年期过早恶化。