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.

尿路阻塞会导致肾脏损伤，如果不矫正，可能会导致不可逆的肾脏损失特别是在婴儿中。新生儿阻塞性肾病的病理生理学一直是相当大的重点数十年来的研究兴趣，但在理解方面的巨大差距包括基于的血管机制肾脏微循环的损害。在本应用中，我们提出了一个新颖的概念，以改变新生儿肾血管耐药性（RVR）和急性输尿管阻塞的灌注是通过反应性介导的肽酶内皮蛋白转换酶1的氧驱动的生物合成，该酶1通过蛋白水解处理多个肾脏大内皮蛋白（ET1-3）的血管活性同工型。 ET来源的肾二酰基甘油（DAG）激活肾脏血管平滑肌细胞TRPC3通道，导致受体经营的细胞外钙进入，长时间的血管收缩，RVR升高和灌注不足。为了调查这些概念，我们将利用在重症监护下维持的新生猪作为可逆尿路阻塞的临床前模型在婴儿中。这些猪和新型的TRPC3基因敲除新生大鼠菌株将用于描述钙依赖性介导的肾血管平滑肌细胞中的信号转导机制1）持续下降灌注， 2）肾脏损伤，3）在急性尿路阻塞期间和之后，肌源性肾脏自动调节受损。本应用程序中提出的研究将获得机械数据，这不仅会改善我们的理解新生儿肾血管病，但可能导致潜在的诊断标记或阻塞性治疗靶标新生儿的肾功能不全。