Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction
Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction
复制标题
腺苷酸活化蛋白激酶去磷酸化通过线粒体功能障碍加重缺血/再灌注诱导的急性肾损伤
DOI：
10.1016/j.kint.2021.10.028
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发表时间：
2022-01-19
影响因子：
19.6
通讯作者：
Li, Jingya
中科院分区：
文献类型：
--
作者：
Ma, Haijian;Guo, Xiaozhen;Li, Jingya
肾小管上皮细胞是高能量消耗的上皮细胞，其主要依赖于脂肪酸氧化来提供能量。AMP活化蛋白激酶（AMPK）是大多数细胞中能量产生的关键调节因子，但AMPK在急性肾脏疾病中肾小管上皮细胞中的功能尚不清楚。在此，我们发现在体内和体外模型中，缺血/再灌注后Thr 172-AMPKa磷酸化迅速降低。肾小管上皮细胞特异性AMPKa缺失的小鼠在缺血/再灌注后表现出加重的肾损伤和肾小管上皮细胞凋亡。AMPKa缺乏伴随着缺血/再灌注损伤后肾小管中脂滴的积聚以及神经酰胺和游离脂肪酸水平的升高。机械地，缺血/再灌注触发神经酰胺产生和激活蛋白磷酸酶PP 2A，其使Thr 172-AMPKa去磷酸化。降低AMPK活性自噬并阻碍功能障碍的线粒体的清除。通过去磷酸化作用靶向PP 2A-AMPK轴，促进线粒体自噬过程。因此，我们的研究表明，AMPKa在急性肾损伤治疗中保护肾小管上皮细胞免受损伤中起重要作用。
Kidney tubular epithelial cells are high energy-consuming epithelial cells that depend mainly on fatty acid oxidation for an energy supply. AMP-activated protein kinase (AMPK) is a key regulator of energy production in most cells, but the function of AMPK in tubular epithelial cells in acute kidney disease is unclear. Here, we found a rapid decrease in Thr172-AMPKa phosphorylation after ischemia/reperfusion in both in vivo and in vitro models. Mice with kidney tubular epithelial cell-specific AMPKa deletion exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after ischemia/reperfusion. AMPKa deficiency was accompanied by the accumulation of lipid droplets in the kidney tubules and the elevation of ceramides and free fatty acid levels following ischemia/reperfusion injury. Mechanistically, ischemia/reperfusion triggered ceramide production and activated protein phosphatase PP2A, which dephosphorylated Thr172-AMPKa. Decreased AMPK activity autophagy and impeded clearance of the dysfunctional mitochondria. Targeting the PP2A-AMPK axis by the dephosphorylation and promoting the mitophagy process. Thus, our study reveals that AMPKa plays an important role in protecting against tubular epithelial cell injury in for acute kidney injury treatment.