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

大量证据表明，产前事件对发育有影响，导致成年后的病理生理后果。其中一些影响的结果是容易患上某些疾病，包括高血压。我们来自前一个资助期的数据表明，在怀孕的关键阶段(肾脏形成的高峰期)，产前接触临床相关剂量的糖皮质激素会减少肾单位的数量，损害盐负荷的排泄(这是性别相关的)，并在成年后升高血压。虽然钠排泄改变的机制几乎不存在，但我们已经报道的肾内肾素-血管紧张素系统(RAS)的改变可能与此有关。此外，目前尚不清楚肾脏发育和肾内RAS的变化是否会导致肾脏损伤的易感性增加，并在第二次侮辱后导致更大的功能丧失。因此，这一拟议项目有两个目标。第一个是确定导致钠负荷排泄能力降低的机制是否与肾脏中对血管紧张素肽做出反应的受体/信号通路的变化有关。第二个是确定产前接触倍他米松是否会导致出生后不良事件造成额外肾脏损害的风险增加。我们将研究绵羊，因为它们在肾脏发生的时间上与人类相似，相对于妊娠阶段，因为这些动物为我们的体外研究提供了足够的肾脏组织。我们假设：1)钠负荷排泄能力降低的机制包括ANG多肽激活与钠尿相关的信号通路的能力降低；以及2)产前暴露倍他米松会导致更大的肾脏损伤风险和第二次出生后功能下降。我们将使用特定的分析方法来测量血管紧张素肽和由它们激活的与钠尿相关的信号通路中的关键成分。结合试验将用于评估这些多肽的受体。我们将使用单侧肾切除或肥胖(由自愿暴饮暴食引起)作为第二次“打击”，评估肾功能和肾脏损伤的标志，以确定产前倍他米松与随后的肾脏损伤是否存在易感关系。了解更多关于产前糖皮质激素对成年后肾功能和肾脏损伤易感性的影响是很重要的，因为糖皮质激素在当今产科中的广泛使用。我们的研究可能会发现，随着肾病和高血压的成熟，他们患肾脏疾病和高血压的风险更高，这可能会导致监测这一高危人群的方法，并早期干预，以防止成年后肾功能的过早恶化。

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.