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

• 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
• 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

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.

尿路梗阻会导致肾脏损伤，如果不加以纠正，可能会导致不可逆的肾脏损失