Kierulf-Lassen Casper, Nielsen Per Mose, Qi Haiyun, Damgaard Mads, Laustsen Christoffer, Pedersen Michael, Krag Søren, Birn Henrik, Nørregaard Rikke, Jespersen Bente
Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
PLoS One. 2017 Dec 21;12(12):e0190009. doi: 10.1371/journal.pone.0190009. eCollection 2017.
While unilateral nephrectomy (UNx) is suggested to protect against ischemia-reperfusion injury (IRI) in the remaining kidney, the mechanisms underlying this protection remain to be elucidated. In this study, functional MRI was employed in a renal IRI rat model to reveal global and regional changes in renal filtration, perfusion, oxygenation and sodium handling, and microarray and pathway analyses were conducted to identify protective molecular mechanisms. Wistar rats were randomized to either UNx or sham UNx immediately prior to 37 minutes of unilateral renal artery clamping or sham operation under sevoflurane anesthesia. MRI was performed 24 hours after reperfusion. Blood and renal tissue were harvested. RNA was isolated for microarray analysis and QPCR validation of gene expression results. The perfusion (T1 value) was significantly enhanced in the medulla of the post-ischemic kidney following UNx. UNx decreased the expression of fibrogenic genes, i.a. Col1a1, Fn1 and Tgfb1 in the post-ischemic kidney. This was associated with a marked decrease in markers of activated myofibroblasts (Acta2/α-Sma and Cdh11) and macrophages (Ccr2). This was most likely facilitated by down-regulation of Pdgfra, thus inhibiting pericyte-myofibroblast differentiation, chemokine production (Ccl2/Mcp1) and macrophage infiltration. UNx reduced ischemic histopathologic injury. UNx may exert renoprotective effects against IRI through increased perfusion in the renal medulla and alleviation of the acute pro-inflammatory and pro-fibrotic responses possibly through decreased myofibroblast activation. The identified pathways involved may serve as potential therapeutic targets and should be taken into account in experimental models of IRI.
虽然单侧肾切除术（UNx）被认为可保护剩余肾脏免受缺血再灌注损伤（IRI），但其保护机制仍有待阐明。在本研究中，功能磁共振成像被应用于肾IRI大鼠模型，以揭示肾脏滤过、灌注、氧合和钠处理的整体及局部变化，并进行基因芯片和通路分析以确定保护的分子机制。在七氟醚麻醉下，Wistar大鼠在单侧肾动脉夹闭37分钟或假手术前立即随机分为UNx组或假UNx组。再灌注24小时后进行磁共振成像。采集血液和肾组织。分离RNA用于基因芯片分析和基因表达结果的定量聚合酶链反应验证。UNx后，缺血后肾脏髓质的灌注（T1值）显著增强。UNx降低了缺血后肾脏中促纤维化基因（即Col1a1、Fn1和Tgfb1）的表达。这与活化肌成纤维细胞（Acta2/α-Sma和Cdh11）和巨噬细胞（Ccr2）标志物的显著减少有关。这很可能是通过下调Pdgfra来促进的，从而抑制周细胞-肌成纤维细胞分化、趋化因子产生（Ccl2/Mcp1）和巨噬细胞浸润。UNx减轻了缺血性组织病理学损伤。UNx可能通过增加肾髓质灌注以及可能通过减少肌成纤维细胞活化来减轻急性促炎和促纤维化反应，从而对IRI发挥肾脏保护作用。所确定的相关通路可能作为潜在的治疗靶点，在IRI实验模型中应予以考虑。
