Regulation of neonatal renal hemodynamics

新生儿和成人肾脏之间的差异不仅限于它们的大小。出生时，新生儿肾脏功能不成熟，与成人相比，表现出较高的血管阻力和较低的肾小球滤过率（GFR）。肾不成熟使新生儿处于肾损伤的风险中，特别是当肾血流动力学被不良围产期事件改变时，包括低血容量、窒息、败血症和肾缺血。新生儿肾脏血流动力学的几个领域仍然没有探索。特别是，机制控制新生儿肾血管张力和病理改变的基础低灌注诱导的急性肾损伤（阿基）尚未解决。越来越多的证据表明，瞬时受体电位（TRP）离子通道家族的成员有助于成人血管张力的内在调节。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。本申请源自初步发现，表明香草素瞬时受体电位（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，并调节肾血管张力、肾灌注和GFR。来自我们的初步研究的数据还表明，肾血管TRPV 4通道表达的改变与肾缺血/再灌注诱导的新生儿阿基相关。该提议的首要假设是TRPV 4通道调节新生儿肾血管阻力和血流动力学，并且肾血管TRPV 4通道表达和活性的改变放大了新生儿阿基中的肾灌注不足。为了解决这一假设，将使用新生猪研究三种特定目的。我们建议：1）研究TRPV 4通道在肾小球前血管肌细胞中的定位，并检验这些通道调节新生儿肾血管阻力的假设，2）确定TRPV 4通道在新生儿肾局部微循环、GFR以及水和电解质稳态中的功能意义，和3）探索新生儿肾缺血/再灌注改变血管肌细胞TRPV 4通道表达和活性的假设，导致肾脏灌注不足和阿基。本申请将确定TRPV 4作为新生儿肾功能的重要调节因子。

The differences between neonatal and adult kidneys are not limited to their sizes. 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 of 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 underlie hypoperfusion-induced acute kidney injury (AKI) are unresolved. 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 in adults. Whether TRP channels control neonatal renal vascular resistance and hemodynamics is unclear. The present application derives from preliminary findings suggesting that the vanilloid transient receptor potential (TRPV) subfamily, member 4 is expressed in neonatal renal preglomerular artery and arteriole myocytes and regulates renal vascular tone, kidney perfusion, and GFR. Data from our pilot studies also suggest that alterations in renal vascular TRPV4 channel expression are associated with renal ischemia/reperfusion-induced neonatal AKI. The overarching hypothesis of this proposal is that TRPV4 channels regulate neonatal renal vascular resistance and hemodynamics, and that alterations in renal vascular 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 propose to: 1) study localization of TRPV4 channels in preglomerular vascular myocytes and test the hypothesis that these channels regulate renal vascular resistance in neonates, 2) determine the functional significance of TRPV4 channels in neonatal renal regional microcirculation, GFR, and water and electrolyte homeostasis, and 3) explore the hypothesis that renal ischemia/reperfusion in neonates alters vascular myocyte TRPV4 channel expression and activity, leading to kidney hypoperfusion and AKI. This application will identify TRPV4 as an important regulator of renal functions in neonates.