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. 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. 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-β1 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. 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.

中文翻译：

---

小鼠单侧肾缺血再灌注损伤中的“无归点”

在过去的几年中，有关慢性肾脏疾病和急性肾脏损伤的相互联系的证据不断增长。潜在的病理生理机制仍不清楚。我们假设，单侧缺血/再灌注损伤中的阈值缺血时间设定了缺血性小管坏死的程度，这是“无返点”导致进行性损伤。这种进展暂时与炎症标志物增加有关，并导致缺血性肾脏的纤维化和萎缩。在不同缺血时间（15、25、35和45分钟）的雄性C57BL / 6 N小鼠中，单侧缺血/再灌注损伤可引起急性肾小管坏死。在15分钟到5周的多个时间点，我们评估了损伤，炎症和纤维化，组织学上的肾小管损伤，细胞死亡（TUNEL），巨噬细胞，中性粒细胞大量涌入和肾脏萎缩。单侧缺血15和25分钟诱导再灌注24 h后损伤标记物上调，但5周后无上调。除Il-6外，在缺血后24小时或5周第15和25分钟，炎症或纤维化的标记均未在基因表达水平上调。在24小时和5周时，缺血35和45分钟持续诱导炎症，损伤和部分纤维化标记物（Tgf-β1和Col1a1）上调。持续性损伤的缺血阈值时间为35分钟，导致炎症和损伤标记物在10 d的过程中出现峰值，时间在6 h至7 d之间。在整个观察过程中，此缺血时间还导致持续的细胞死亡（TUNEL），持续5周，在6 h达到峰值，并在缺血后7 d开始进展性肾萎缩。这项研究证实了缺血性损伤阈值程度的证据，其中损伤，炎症和纤维化的指标并未下降至基线，但长期结果（5周）评估仍保持上调。超过此阈值的“无归来点”会导致细胞持续死亡和进行性萎缩，其特征是炎症和损伤的标志物在时间上具有关联性。