Vascular ion channels and microcirculation in neonatal urinary tract obstruction

尿路梗阻引起肾损伤，如果不纠正，可能导致不可逆的肾功能丧失 尤其是在婴儿中。新生儿梗阻性肾病的病理生理一直是一个相当大的焦点， 几十年来，研究兴趣，但在理解方面存在重大差距，包括血管机制， 肾微循环障碍。在本申请中，我们提出了一种新颖的概念， 新生儿肾血管阻力（RVR）和急性输尿管梗阻的灌注是由反应性 氧物种驱动的肽酶内皮素转化酶1的生物合成，其蛋白水解处理 多种肾大内皮素（ET 1 -3）对其血管活性亚型的影响。ET衍生的肾二酰甘油（DAG）激活 肾血管平滑肌细胞TRPC 3通道，导致受体操作的细胞外钙进入， 血管收缩延长、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维持的新生猪 在婴儿身上。这些猪和一种新的TRPC 3敲除新生大鼠品系将用于描述钙依赖性 肾血管平滑肌细胞介导1）持续低灌注， 2)肾损伤; 3）急性尿路梗阻期间和之后的肌源性肾自身调节受损。 这项申请中提出的研究将积累机制数据，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物或治疗目标的梗阻性 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.