Imprint Osmoregulation/Maternally-Dehydrated Offspring

描述（由候选人提供）： 妊娠引起了显著的生理适应的组成和容量的流体室。在人类和大鼠妊娠期间，母体血容量增加，血浆渗透压降低。由于剧烈呕吐、运动或脱水，未能充分“重置”母体血浆渗透压或暴露于母体血浆高渗，导致胎儿血浆渗透压增加，这刺激胎儿精氨酸加压素（AVP）分泌，导致羊水（AF）量减少。相反，诱导的母体血浆低渗降低了胎儿血浆渗透压，增加了胎儿尿流量，减少了胎儿吞咽，并增加了羊和人类的AF体积。更重要的是，慢性子宫内血浆张力改变会影响新生大鼠和人类的肾脏调节和肾脏反应，包括AVP合成和分泌，以及可能的血压。转录调节的印记可能增加新生儿和/或成人对水/电解质失衡、高血压和冠心病的易感性。也有可能的是，印记的血浆渗透压调节可能具有代际效应，使得雌性后代在随后的怀孕期间可能无法适当地重置其血浆渗透压并充分地扩大其血浆体积。我们对大鼠的初步研究表明，母亲在怀孕期间脱水会导致新生儿高钠血症和高渗。我们假设母体脱水改变了新生儿和成年后代的基础血浆张力，其原因是：（1）中枢AVP受体核的AVP调节设定点升高，细胞体积调节改变，或（2）基础AVP mRNA和合成减少，AVP分泌减少，和/或（3）AVP诱导的肾脏抗利尿作用减少。我们建议检查中央和外周机制的印记的AVP-精氨酸甲酯调节系统。我们将确定分子和细胞机制和外周肾AVP受体的变化。最后，我们将描绘的关键时期，在此期间，AVP/AVP调节通路的印记发生。

DESCRIPTION (provided by candidate): Pregnancy evokes marked physiologic adaptations in the composition and volume of fluid compartments. During human and rat pregnancy, maternal blood volume increases and plasma osmolality decreases. Failure to adequately "reset" maternal plasma osmolality or exposure to maternal plasma hypertonicity, as a result of hyperemesis, exercise or dehydration, results in increased fetal plasma osmolality, which stimulates fetal arginine vasopressin (AVP) secretion, causing reduced amniotic fluid (AF) volume. Conversely, induced maternal plasma hypotonicity reduces fetal plasma osmolality, increases fetal urine flow, reduces fetal swallowing and increases AF volume in sheep and humans. More importantly, chronic in utero plasma tonicity alterations imprint newborn rat and human osmoregulation and renal responses including AVP synthesis and secretion, and possibly blood pressure. The imprinting of osmoregulation may increase the susceptibility of the newborn and/or adult to water/electrolyte imbalance, hypertension and coronary heart disease. It is also possible that the imprinted osmoregulation may have intergenerational effects such that the female offspring may not appropriately reset their plasma osmolality and adequately expand their plasma volume during their subsequent pregnancies. Our preliminary studies of rats indicate that maternal dehydration during pregnancy results in hypernatremia and hypertonicity in the newborn. We hypothesize that maternal dehydration alters basal plasma tonicity in newborn and adult offspring, as a result of: (1) an elevated osmoregulatory set-point of the central osmoreceptor nuclei, and altered cellular volume regulation or (2) reduced basal AVP mRNA and synthesis, and AVP secretion in response to osmotic stimuli, and/or (3) reduced AVP-induced renal antidiuresis. We propose to examine central and peripheral mechanisms for the imprinting of the AVP-osmoregulatory system. We will determine the molecular and cellular mechanism(s) and peripheral renal AVP receptor changes. Finally, we will delineate the critical period during which imprinting of the AVP/osmoregulatory pathway occurs.