Scotland Kymora B, Almutairi Khaled, Park Elliya, Wang Lu, Kung Sonia H Y, Haegert Anne, Adomat Hans, Bell Robert, LeBihan Stephane, Chew Ben H, Lange Dirk
Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.
Department of Urologic Sciences, The Stone Centre at Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
BJU Int. 2023 Mar;131(3):367-375. doi: 10.1111/bju.15912. Epub 2022 Nov 1.
To investigate global changes in ureters at the transcriptional, translational and functional levels, both while stents are indwelling and after removal and recovery, and to study the effects of targeting pathways that play a potential role.
Pig ureters were stented for varying amounts of time (48 h, 72 h, 14 days) and the impact on peristalsis, dilatation and hydronephrosis were assessed. RNAseq, proteomic, histological and smooth muscle (SM) function analyses were performed on ureteric and kidney tissues to assess changes induced by stenting and recovery. Pathway analysis was performed using Ingenuity Pathway Analysis software. To study the impact of possible interventions, the effects of erythropoeitin (EPO) and a Gli1 inhibitor were assessed.
Stenting triggers massive ureteric dilatation, aperistalsis and moderate hydronephrosis within 48 h. Pathways associated with obstruction, fibrosis and kidney injury were upregulated by stenting. Increased expression of GLI1, clusterin-α (a kidney injury marker) and collagen 4A2 (a fibrosis marker) was found in stented vs contralateral unstented ureters. EPO did not improve peristalsis or contraction force but did decrease non-purposeful spasming seen exclusively in stented ureters. Tamsulosin administration increased contractility but not rate of peristalsis in stented ureters.
Ureters respond to stents similarly to how they respond to an obstruction, that is, with activation of pathways associated with hydronephrosis, fibrosis and kidney injury. This is driven by significant dilatation and associated ureteric SM dysfunction. EPO and tamsulosin induced mild favourable changes in SM physiology, suggesting that targeting specific pathways has potential to address stent-induced complications.
研究输尿管在支架留置期间、取出及恢复后在转录、翻译和功能水平上的整体变化，并研究靶向发挥潜在作用的信号通路的影响。
对猪输尿管进行不同时长（48小时、72小时、14天）的支架置入，评估其对蠕动、扩张和肾积水的影响。对输尿管和肾脏组织进行RNA测序、蛋白质组学、组织学和平滑肌（SM）功能分析，以评估支架置入和恢复所诱导的变化。使用Ingenuity Pathway Analysis软件进行信号通路分析。为研究可能干预措施的影响，评估了促红细胞生成素（EPO）和Gli1抑制剂的作用。
支架置入在48小时内引发输尿管大量扩张、蠕动消失和中度肾积水。与梗阻、纤维化和肾损伤相关的信号通路因支架置入而上调。在置入支架的输尿管与对侧未置入支架的输尿管中，发现GLI1、簇集素-α（一种肾损伤标志物）和胶原蛋白4A2（一种纤维化标志物）的表达增加。EPO并未改善蠕动或收缩力，但确实减少了仅在置入支架的输尿管中出现的无目的痉挛。坦索罗辛给药增加了置入支架输尿管的收缩力，但未提高蠕动速率。
输尿管对支架的反应与对梗阻的反应相似，即通过激活与肾积水、纤维化和肾损伤相关的信号通路。这是由显著扩张及相关的输尿管平滑肌功能障碍所驱动。EPO和坦索罗辛在平滑肌生理方面诱导了轻微的有利变化，表明靶向特定信号通路有可能解决支架诱导的并发症。
