BackgroundDamage to the endothelium due to ischemia reperfusion injury (IRI) leads to a disruption of the microvasculature, which could be influenced by angiopoietin 1 via its effects on endothelium. We investigated the physiological and therapeutic roles of angiopoietin 1 in renal IRI using angiopoietin 1 knockout and over-expression mice.MethodsRenal IRI was induced by clamping the right renal artery seven days after left uninephrectomy for 25 min followed by reperfusion. A whole body angiopoietin 1 knockout was achieved by induction with tamoxifen. The renal tubule over-expression of angiopoietin 1 was induced by doxycycline.ResultsIn the normal mice, the renal expression of angiopoietin 1 increased 7 days to 14 days after IRI. The angiopoietin 1 knockout caused a delay in the recovery of renal function, less tubular regeneration and more residual tubular necrosis. The endothelial density was lower and the VE-cadherin protein loss was greater in the knockout mice. The over-expression of angiopoietin 1 attenuated the tubular necrosis and renal function impairment 1 and 3 days after IRI. The loss of the endothelium was ameliorated in the over-expression mice. This protective effect was associated with the up-regulation of the gene expression of epidermal growth factor, hepatocyte growth factor, and insulin like growth factor-1 and less tubular apoptosis. The over-expression of angiopoietin 1 stimulated tumor necrosis factor-α, C-C chemokine receptor type 2 and CX3C chemokine receptor 1 inflammatory gene expression, but did not influence macrophage infiltration.ConclusionsAltogether, the augmentation and downregulation of angiopoietin 1 attenuated renal damage and impaired renal recovery, respectively, by influencing the survival/regeneration of the endothelium. The manipulation of angiopoietin 1 represents a novel therapeutic approach for the treatment of ischemic kidney injury.

中文翻译：

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血管生成素 1 通过调节内皮存活和再生影响缺血再灌注肾损伤

背景由于缺血再灌注损伤 (IRI) 对内皮的损害会导致微血管系统的破坏，这可能会受到血管生成素 1 对内皮的影响。我们使用血管生成素 1 敲除和过表达小鼠研究了血管生成素 1 在肾 IRI 中的生理和治疗作用。方法通过在左单肾切除术 7 天后夹住右肾动脉 25 分钟然后再灌注来诱导肾 IRI。通过用他莫昔芬诱导实现全身血管生成素 1 敲除。多西环素诱导肾小管过度表达血管生成素1。结果在正常小鼠IRI后7-14天，肾小管血管生成素1的表达增加。血管生成素 1 敲除导致肾功能恢复延迟，较少的肾小管再生和较多的残余肾小管坏死。敲除小鼠的内皮密度较低，VE-钙粘蛋白损失较大。在 IRI 后 1 天和 3 天，血管生成素 1 的过度表达减弱了肾小管坏死和肾功能损害。过表达小鼠的内皮损失得到改善。这种保护作用与表皮生长因子、肝细胞生长因子和胰岛素样生长因子-1 基因表达的上调以及肾小管细胞凋亡减少有关。血管生成素 1 的过表达刺激肿瘤坏死因子-α、CC 趋化因子受体 2 和 CX3C 趋化因子受体 1 炎症基因表达，但不影响巨噬细胞浸润。血管生成素 1 的增强和下调分别通过影响内皮的存活/再生来减轻肾损伤和受损的肾恢复。血管生成素 1 的操作代表了一种治疗缺血性肾损伤的新型治疗方法。