"Point of no return" in unilateral renal ischemia reperfusion injury in mice
"Point of no return" in unilateral renal ischemia reperfusion injury in mice
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DOI：
10.1186/s12929-020-0623-9
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发表时间：
2020-02-14
影响因子：
11
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Holderied, Alexander;Kraft, Franziska;Anders, Hans-Joachim
背景在过去的几年里，越来越多的证据表明慢性肾脏疾病与急性肾损伤之间存在相互联系。其潜在的病理生理机制尚不清楚。我们假设，在单侧缺血/再灌流损伤中，阈值缺血时间设定了缺血小管坏死的程度，作为“不返回点”，这将导致进行性损伤。这一进展暂时与炎症标志物的增加有关，并导致缺血肾脏的纤维化和萎缩。方法雄性C57BL/6N小鼠在不同的缺血时间(15、25、35、45min)，采用单侧缺血/再灌注损伤的方法诱导急性肾小管坏死。在15min至5周的多个时间点，我们评估了损伤、炎症和纤维化、肾小管损伤、细胞死亡(TUNEL)、巨噬细胞、中性粒细胞流入和肾萎缩的组织学标志物的基因表达。结果单侧脑缺血15、25min再灌注2 4h后损伤标志物表达上调，5周后未见上调。除IL-6外，所有炎症或纤维化标志物在缺血后15分钟、25分钟、24小时或5周的基因表达水平均未见上调。缺血35分钟和45分钟持续诱导炎症、损伤和部分纤维化的标志物(转化生长因子-β1和胶原蛋白1a1)在24小时和5周时上调。持续损伤阈值时间35min可诱导炎症和损伤标志物的时间相关性，高峰出现在10d过程中的6h~7d，在整个观察5周过程中也可导致持续性细胞死亡，高峰出现在6h，并在缺血后7d开始进行性肾萎缩。结论本研究证实了缺血性损伤阈值范围的证据，在该阈值范围内，损伤、炎症和纤维化的标记物不会下降到基线水平，但在长期结果(5周)中仍有上调。超过这一阈值的“不返回点”会导致持续的细胞死亡和进行性萎缩，其特点是炎症和损伤的标志物之间存在暂时的联系。
Background In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as "point of no return" leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney. Methods Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy. Results Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-beta 1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia. Conclusions This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as "point of no return" leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury.