Vascular ion channels and microcirculation in neonatal urinary tract obstruction

新生儿尿路梗阻的血管离子通道与微循环

基本信息

批准号：
9884233
负责人：
Adebowale Adebiyi
金额：
$ 51.24万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9884233
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Anabolism Animals Atrophic Big Endothelin Biological Assay Biological Markers Blood Vessels Blood capillaries Calcium Childhood Chronic Kidney Failure Data Development Diagnostic Diglycerides Disease EDN1 gene Electrophysiology (science)Endothelin Endothelin Receptor Endothelin-1 Endothelin-2 Endothelin-3 Endothelin-converting enzyme 1 Event Family suidae Fibrosis Functional disorder Glomerular Filtration Rate Histologic Homeostasis Image Impairment Infant Inflammation Injury to Kidney Intensive Care Intervention Ion Channel Kidney Kidney Diseases Kidney Failure Knock-out Lead Left Link Mediating Microcirculation Modeling Myography NADPH Oxidase Neonatal Newborn Infant Obstruction Outcome Study Pathway interactions Peptide Hydrolases Perfusion Perinatal Pharmacology Physiological Pilot Projects Pre-Clinical Model Process Production Protein Isoforms Proteolytic Processing Rat Strains Rattus Reactive Inhibition Reactive Oxygen Species Receptor Activation Regional Blood Flow Renal function Research Signal Transduction Smooth Muscle Myocytes TRPC3 ion channel Techniques Testing Time Study Tubular formation Ureteral obstruction Urine Vascular Diseases Vascular Smooth Muscle Vascular resistance Vasodilation Weaning cohort diagnostic biomarker epithelial to mesenchymal transition extracellular hemodynamics hypoperfusion improved inhibitor/antagonist innovation interest invention kidney vascular structure multiphoton microscopy neonate novel patch clamp pre-clinical pressure prevent protein expression real-time images receptor receptor operated channel therapeutic target urinary urinary tract obstruction vasoconstriction

项目摘要

Urinary tract obstruction causes kidney injury, which, if left uncorrected, may lead to an irreversible renal loss especially in infants. The pathophysiology of neonatal obstructive nephropathy has been a focus of considerable research interests for decades, but significant gaps in understanding include vascular mechanisms that underlie impairment of renal microcirculation. In the present application, we propose a novel concept that alterations of newborn renal vascular resistance (RVR) and perfusion by acute ureteral obstruction are mediated by reactive oxygen species-driven biosynthesis of peptidase endothelin-converting enzyme 1, which proteolytically processes multiple renal big endothelins (ET1-3) to their vasoactive isoforms. ET-derived renal diacylglycerol (DAG) activates renal vascular smooth muscle cell TRPC3 channels, leading to receptor-operated extracellular calcium entry, prolonged vasoconstriction, RVR elevation, and hypoperfusion. To investigate these concepts, we will utilize newborn pigs that are maintained under intensive care as a preclinical model for reversible urinary tract obstruction in infants. These pigs and a novel TRPC3 knockout neonatal rat strain will be used to delineate calcium-dependent signal transduction mechanisms in renal vascular smooth muscle cells that mediate 1) persistent hypoperfusion, 2) kidney injury, and 3) impaired myogenic renal autoregulation during and after acute urinary tract obstruction. The proposed studies in this application will accrue mechanistic data that will not only improve our understanding of neonatal renal vasculopathy but may lead to potential diagnostic markers or therapeutic targets for obstructive renal insufficiency in newborns.

尿路梗阻会导致肾损伤，如果不及时纠正，可能会导致不可逆的肾功能丧失尤其是婴儿。新生儿梗阻性肾病的病理生理学一直是人们关注的焦点几十年来的研究兴趣，但对血管机制的理解存在重大差距肾脏微循环障碍。在本申请中，我们提出了一个新的概念，即改变新生儿肾血管阻力（RVR）和急性输尿管梗阻引起的灌注是由反应性介导的氧物质驱动的肽酶内皮素转化酶 1 的生物合成，该酶进行蛋白水解过程多种肾大内皮素 (ET1-3) 与其血管活性亚型。 ET 衍生的肾二酰甘油 (DAG) 激活肾血管平滑肌细胞 TRPC3 通道，导致受体操纵的细胞外钙进入，长时间的血管收缩、RVR 升高和灌注不足。为了研究这些概念，我们将利用作为可逆性尿路梗阻的临床前模型，在重症监护下饲养的新生猪在婴儿中。这些猪和一种新型 TRPC3 敲除新生大鼠品系将用于描述钙依赖性肾血管平滑肌细胞的信号转导机制介导1）持续性低灌注， 2) 肾损伤，以及 3) 急性尿路梗阻期间和之后肌源性肾自动调节受损。本申请中提出的研究将积累机械数据，这不仅会提高我们的理解新生儿肾血管病的研究，但可能导致阻塞性肾病的潜在诊断标志物或治疗靶点新生儿肾功能不全。