Vascular ion channels and microcirculation in neonatal urinary tract obstruction

尿路梗阻会导致肾脏损伤，如果不加以纠正，可能会导致不可逆转的肾功能丧失。 尤其是在婴儿身上。新生儿梗阻性肾病的病理生理学研究一直是人们关注的焦点。 几十年来的研究兴趣，但在理解方面的重大差距包括基础的血管机制 肾微循环障碍。在本申请中，我们提出了一种新的概念，即改变 反应性介导的新生儿肾血管阻力(RVR)和急性输尿管梗阻的血流灌注 氧物种驱动的蛋白水解性多肽酶-内皮素转换酶1的生物合成 多个肾脏大内皮素(ET1-3)与其血管活性亚型有关。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内流， 长时间血管收缩、RVR升高和低灌流。为了研究这些概念，我们将利用 新生猪在重症监护下作为可逆性尿路梗阻的临床前模型 在婴儿身上。这些猪和一种新的TRPC3基因敲除的新生大鼠品系将被用来描述钙依赖 肾血管平滑肌细胞中介导1)持续性低灌注率的信号转导机制， 2)肾损伤；3)急性尿路梗阻时及梗阻后肌源性肾自动调节功能受损。 本申请中拟议的研究将获得机械性数据，这些数据不仅将提高我们的理解 新生儿肾血管病变，但可能导致潜在的诊断标志或治疗靶点的梗阻 新生儿肾功能不全。

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.