Regulation of neonatal renal hemodynamics

新生儿肾脏血流动力学的调节

• 批准号: 9303346
• 负责人: Adebowale Adebiyi
• 金额: $ 30万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303346
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Agonist; Area; Arteries; Asphyxia; Attenuated; Birth; Blood Vessels; Blood flow; Calcium Channel; Cations; Data; Electrolytes; Electrophysiology (science); Event; Excretory function; Exhibits; Family; Family suidae; Glomerular Filtration Rate; Homeostasis; Hypovolemia; Image; Injury; Ion Channel; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Laser-Doppler Flowmetry; Liquid substance; Maintenance; Measures; Membrane; Microcirculation; Modeling; Muscle Cells; Myography; Neonatal; Newborn Infant; Organ; Pathologic; Pathway interactions; Perfusion; Perinatal; Pharmacology; Physiological; Pilot Projects; Plasma; Preventive; Process; RNA Interference; Regional Perfusion; Regulation; Renal Blood Flow; Reperfusion Therapy; Risk; Role; Sepsis; Stretching; Techniques; Testing; Therapeutic; Time; Tubular formation; Ultrasonography; Up-Regulation; Vanilloid; Vascular resistance; arteriole; constriction; experimental study; glomerular function; hemodynamics; hypoperfusion; instrument; kidney vascular structure; member; meter; neonate; new therapeutic target; novel; pressure; protein expression; public health relevance; receptor; renal artery; renal ischemia; response; urinary; vasoconstriction; voltage

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.

描述（申请人提供）：出生时，新生儿肾脏功能尚未成熟，与成人相比，血管阻力更高，肾小球滤过率（GFR）更低。肾脏不成熟使新生儿面临肾损伤的风险，特别是当肾脏血流动力学因围产期不良事件（包括低血容量、窒息、败血症和肾缺血）而改变时。新生儿肾脏血流动力学的几个领域仍有待探索。特别是，控制新生儿肾血管张力和导致急性肾损伤（AKI）期间灌注不足的病理改变的机制尚不清楚。越来越多的证据表明，离子通道瞬时受体电位 (TRP) 家族的成员有助于血管张力和器官血流的内在调节。 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。本申请源于初步发现，表明香草酸瞬时受体电位(TRPV)亚家族成员4在新生儿肾小球前肾动脉和小动脉肌细胞中表达，并调节肌源性血管收缩、局部肾灌注和GFR。我们的初步研究数据还表明，肾血管 TRPV4 通道表达的改变与肾缺血/再灌注诱发的新生儿 AKI 中的肾脏灌注不足有关。该提议的总体假设是，血管肌细胞 TRPV4 通道的激活有助于新生儿肾血流自动调节，而肾血管肌细胞 TRPV4 通道表达和活性的改变会加剧新生儿 AKI 中的肾脏灌注不足。为了解决这一假设，将使用新生猪来研究三个具体目标。我们将检验以下假设：1. 血管内压激活肌细胞 TRPV4 通道，导致新生儿肾小球前动脉膜去极化和血管收缩，2. 肌细胞 TRPV4 通道调节新生儿肾微循环、GFR 和电解质稳态，以及 3. 新生儿肾缺血再灌注 上调动脉肌细胞 TRPV4 通道表达和活性，导致灌注不足和 GFR 降低。该应用将确定 TRPV4 通道作为新生儿肾小球功能的重要调节剂。