Regulation of neonatal renal hemodynamics

描述(申请人提供)：出生时，新生儿肾脏功能不成熟，与成人相比，表现出更高的血管阻力和更低的肾小球滤过率(GFR)。肾脏不成熟使新生儿面临肾脏损伤的风险，特别是当肾血流动力学因围产期不良事件而改变时，包括低血容量、窒息、败血症和肾脏缺血。新生儿肾脏血流动力学的几个领域仍未被研究。特别是，控制新生儿肾血管张力的机制和导致急性肾损伤(AKI)时低灌注量的病理变化尚不清楚。越来越多的证据表明，瞬时受体电位(Trp)家族的离子通道成员对血管张力和器官血流的内在调节起着重要作用。Trp通道是否控制新生儿肾血管阻力和血流动力学尚不清楚。目前的应用源于初步发现，香草样瞬时受体潜力(TRPV)亚家族成员4在新生儿肾小球前动脉和小动脉肌细胞中表达，调节肌源性血管收缩、局部肾脏灌流和GFR。我们前期研究的数据还表明，肾血管TRPV4通道表达的改变与肾脏缺血/再灌流诱导的新生儿AKI的肾脏低灌注量有关。该方案的基本假设是，血管肌细胞TRPV4通道的激活有助于新生儿肾血流的自动调节，肾血管肌细胞TRPV4通道的表达和活性的改变放大了新生儿AKI的肾脏低灌注量。为了解决这一假设，将使用新生的猪来研究三个具体目标。我们将验证如下假设：1.血管内压激活心肌细胞TRPV4通道，导致新生肾小球前动脉膜去极化和血管收缩；2.心肌细胞TRPV4通道调节新生儿肾脏微循环、GFR和电解质稳态；3.新生儿肾脏缺血再灌流上调动脉TRPV4通道的表达和活性，导致低灌注量和GFR减少。这项应用将确定TRPV4通道是新生儿肾小球功能的重要调节器。

DESCRIPTION (provided by applicant): At birth, the newborn kidneys are functionally immature and exhibit higher vascular resistance and lower glomerular filtration rate (GFR) compared with adults. Renal immaturity put neonates at risk for kidney injury, especially when renal hemodynamics is altered by adverse perinatal events including hypovolemia, asphyxia, sepsis, and renal ischemia. Several areas of neonatal renal hemodynamics remain unexplored. In particular, mechanisms that control neonatal renal vascular tone and pathological alterations that result in hypoperfusion during acute kidney injury (AKI) are unclear. A growing body of evidence suggests that members of the transient receptor potential (TRP) family of ion channels contribute to the intrinsic regulation of vascular tone and organ blood flow. Whether TRP channels control neonatal renal vascular resistance and hemodynamics is unknown. The present application originates from preliminary findings suggesting that the vanilloid transient receptor potential (TRPV) subfamily, member 4 is expressed in neonatal preglomerular renal artery and arteriole myocytes and regulates myogenic vasoconstriction, regional kidney perfusion, and GFR. Data from our pilot studies also suggest that alterations in renal vascular TRPV4 channel expression are associated with kidney hypoperfusion in renal ischemia/reperfusion-induced neonatal AKI. The overarching hypothesis of this proposal is that activation of vascular myocyte TRPV4 channels contributes to neonatal renal blood flow autoregulation, and that alterations in renal vascular myocyte TRPV4 channel expression and activity amplify kidney hypoperfusion in neonatal AKI. To address this hypothesis, three Specific Aims will be studied using newborn pigs. We will test the hypotheses that: 1. Intravascular pressure activates myocyte TRPV4 channels, leading to membrane depolarization and vasoconstriction in neonatal renal preglomerular arteries, 2. Myocyte TRPV4 channels regulate neonatal renal microcirculation, GFR, and electrolyte homeostasis, and 3. Renal ischemia-reperfusion in neonates upregulates arterial myocyte TRPV4 channel expression and activity, leading to hypoperfusion and a reduction in GFR. This application will identify TRPV4 channels as an important modulator of glomerular functions in neonates.