Regulation of neonatal renal hemodynamics

新生儿肾脏血流动力学的调节

• 批准号: 8879129
• 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/8879129
• 关键词: 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; Health; Homeostasis; Hypovolemia; Image; Injury; Ion Channel; Ischemia; Isotopes; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Laser-Doppler Flowmetry; Liquid substance; Maintenance; Measures; Membrane; Microcirculation; Modeling; Muscle Cells; Myography; Neonatal; Newborn Infant; Organ; Pathway interactions; Perfusion; Perinatal; Physiological; Pilot Projects; Plasma; Preventive; Process; Proteins; RNA Interference; Regional Perfusion; Regulation; Renal Blood Flow; Reperfusion Therapy; Risk; Role; Sepsis; Stretching; TRPV channel; Techniques; Testing; Therapeutic; Time; Tubular formation; Ultrasonography; Up-Regulation; Vanilloid; Vascular resistance; arteriole; constriction; glomerular function; hemodynamics; hypoperfusion; instrument; kidney vascular structure; mRNA Expression; member; meter; neonate; new therapeutic target; novel; pressure; protein expression; receptor; renal artery; renal ischemia; research study; 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（由申请人提供）：出生时，新生儿肾脏功能不成熟，与成人相比，血管阻力较高，肾小球滤过率（GFR）较低。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，控制新生儿肾血管紧张度和病理改变，导致低灌注在急性肾损伤（阿基）还不清楚。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。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中的肾灌注不足相关。该提议的首要假设是，血管肌细胞TRPV 4通道的激活有助于新生儿肾血流自动调节，并且肾血管肌细胞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。我们将测试的假设是：1。血管内压力激活肌细胞TRPV 4通道，导致新生儿肾小球前动脉膜去极化和血管收缩。肌细胞TRPV 4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可上调动脉肌细胞TRPV 4通道表达和活性，导致灌注不足和GFR降低。本申请将鉴定TRPV 4通道作为新生儿肾小球功能的重要调节剂。