Lipocalin-2 protects against renal ischemia/reperfusion injury in mice through autophagy activation mediated by HIF1α and NF-κb crosstalk
Lipocalin-2 protects against renal ischemia/reperfusion injury in mice through autophagy activation mediated by HIF1α and NF-κb crosstalk
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DOI：
10.1016/j.biopha.2018.09.023
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发表时间：
2018-12-01
影响因子：
7.5
通讯作者：
Zhang, Zhaoguang
中科院分区：
文献类型：
--
作者：
Qiu, Shujuan;Chen, Xuexun;Zhang, Zhaoguang
肾缺血/再灌注损伤是急性肾损伤（AKI）的主要原因，会引发与浸润巨噬细胞相关的炎症反应。 Lipocalin-2 (Lcn2) 水平呈正相关，可防止肾缺血/再灌注损伤。然而，其机制仍不清楚。本研究的目的是探讨Lcn2对肾缺血/再灌注损伤的保护机制。我们发现 Lcn2 缺乏显着加重小鼠的肾损伤，表现为血清肌酐升高、形态损伤更严重以及肾小管上皮细胞死亡增加。我们还观察到Lcn2(-/-)小鼠的自噬减弱，与野生型相比，I/R后Lcn2(-/-)小鼠的自噬标记物LC3 II水平显着降低，p62水平增加。从机制上讲，我们发现重组 Lcn2 可在体外减弱缺氧诱导的近曲小管上皮细胞凋亡，而 HIF-1 α 的下调会减弱 Lcn2 诱导的自噬并增强细胞凋亡。此外，Lcn2 在缺氧条件下减弱了 NF-kappa b 亚基 p65 的激活。因此，我们的研究结果使人们更好地了解 Lcn2 在肾脏缺血/再灌注损伤中的保护作用，并表明 Lcn2 可能是治疗 AKI 患者的一个有前途的治疗靶点。
Renal ischemia/reperfusion injury is a main cause of acute kidney injury (AKI) triggering an inflammatory response associated with infiltrating macrophages. Lipocalin-2 (Lcn2) levels correlate positively and protect against renal ischemia/reperfusion injury. However, the mechanisms remain unclear. The aim of study was to investigate the protective mechanisms of Lcn2 on renal ischemia/reperfusion injury. We found that Lcn2 deficiency significantly aggravated renal injury as evidenced by higher serum creatinine, more severe morphological injury, and increased tubular epithelial cell death in mice. We also observed that attenuated autophagy in Lcn2(-/-) mice, as autophagy markers LC3 II level was significantly decreased and p62 was increased in the Lcn2(-/-) mice after I/R, compared with that of wild type. Mechanistically, we found that recombinant Lcn2 attenuated hypoxia-induced apoptosis in proximal tubule epithelial cells in vitro, and downregulation of HIF-1 alpha blunted Lcn2-induced autophagy and enhanced apoptosis. In addition, the Lcn2 attenuated NF-kappa b subunit p65 activation under hypoxia conditions. Thus, our findings provide a better understanding of the protective role of Lcn2 in kidney ischemia/reperfusion injury and suggest that Lcn2 may be a promising therapeutic target for treating patients with AKI.