Regulation of neonatal renal hemodynamics

新生儿肾脏血流动力学的调节

• 批准号: 8671975
• 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/8671975
• 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; Pathway interactions; Perfusion; Perinatal; Physiological; Pilot Projects; Plasma; Preventive; Process; Proteins; RNA Interference; Regional Perfusion; Regulation; Renal Blood Flow; Renal function; Reperfusion Therapy; Risk; Role; Sepsis; Stretching; TRPV channel; Techniques; Testing; Therapeutic; Time; Tubular formation; Ultrasonography; Up-Regulation; Vanilloid; Vascular resistance; Water; arteriole; constriction; 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

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.

新生儿和成人肾脏的差异并不局限于它们的大小。出生时，新生儿肾脏功能不成熟，与成人相比，血管阻力更高，肾小球滤过率（GFR）更低。肾不成熟使新生儿有肾损伤的危险，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未被探索。特别是，控制新生儿肾血管张力的机制和低灌注诱导的急性肾损伤（AKI）的病理改变尚不清楚。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参与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。目前的应用源于初步研究结果，表明香兰素瞬时受体电位（TRPV）亚家族成员4在新生儿肾肾小球前动脉和小动脉肌细胞中表达，并调节肾血管张力、肾脏灌注和GFR。我们的前期研究数据还表明，肾血管TRPV4通道表达的改变与肾缺血/再灌注诱导的新生儿AKI有关。该建议的总体假设是TRPV4通道调节新生儿肾血管阻力和血流动力学，肾血管TRPV4通道表达和活性的改变放大了新生儿AKI肾灌注不足。为了解决这一假设，三个具体目标将研究使用新生猪。我们建议：1)研究肾小球前血管肌细胞中TRPV4通道的定位，验证这些通道调节新生儿肾血管阻力的假说；2)确定TRPV4通道在新生儿肾区域微循环、GFR和水电解质稳态中的功能意义；3)探讨新生儿肾脏缺血/再灌注改变血管肌细胞TRPV4通道的表达和活性，导致肾脏灌注不足和AKI的假说。该应用将确定TRPV4作为新生儿肾脏功能的重要调节因子。