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易患某些疾病，包括高血压。我们先前资助期的数据表明，在妊娠关键阶段（肾形成高峰期）产前暴露于临床相关剂量的糖皮质激素可减少肾单位数量，损害盐负荷的排泄（这是性别依赖的），并使成年后血压升高。虽然关于钠排泄改变的机制的知识几乎不存在，但我们报道的肾内肾素-血管紧张素系统（RAS）的改变可能与此有关。此外，尚不清楚肾脏发育和肾内RAS的改变是否会导致对肾脏损害的更大易感性和第二次损伤后更大的功能丧失。因此，这个拟议的项目有两个目标。首先是确定导致钠负荷排泄能力降低的机制是否涉及肾脏中响应血管紧张素肽的受体/信号通路的改变。第二是确定产前倍他米松暴露是否会导致出生后不良事件导致额外肾损害的风险增加。我们将研究绵羊，因为它们的肾脏形成时间与人类的妊娠阶段相似，因为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)与钠负荷排泄能力降低有关的机制包括Ang肽激活与钠尿相关的信号通路的能力降低；并且，2)产前倍他米松暴露导致肾脏损伤的风险更大，并且在第二次分娩后肾功能下降。我们将使用特定的测定方法来测量血管紧张素肽及其激活的与尿钠相关的信号通路中的关键成分。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）作为第二个“打击”，并评估肾功能和肾损害标志物，以确定产前倍他米松与随后的肾损伤之间是否存在易感关系。由于糖皮质激素在产科的广泛应用，更多地了解产前糖皮质激素对肾功能的影响以及成年后对肾损害的易感性是很重要的。我们的研究可能会确定一个在成熟时肾脏疾病和高血压风险更高的人群，这可能会导致监测这一风险人群和早期干预的方法，以防止成年期肾功能过早恶化。

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.