Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Kidney Int. 2022 Feb;101(2):315-330. doi: 10.1016/j.kint.2021.10.028. Epub 2021 Nov 11.
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-AMPKα phosphorylation after ischemia/reperfusion in both in vivo and in vitro models. Mice with kidney tubular epithelial cell-specific AMPKα deletion exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after ischemia/reperfusion. AMPKα 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-AMPKα. Decreased AMPK activity repressed serine/threonine kinase ULK1-mediated autophagy and impeded clearance of the dysfunctional mitochondria. Targeting the PP2A-AMPK axis by the allosteric AMPK activator C24 restored fatty acid oxidation and reduced tubular cell apoptosis during ischemia/reperfusion-induced injury, by antagonizing PP2A dephosphorylation and promoting the mitophagy process. Thus, our study reveals that AMPKα plays an important role in protecting against tubular epithelial cell injury in ischemia/reperfusion-induced acute kidney injury. Hence, activation of AMPK could be a potential therapeutic strategy for acute kidney injury treatment.
肾小管上皮细胞是高耗能的上皮细胞，主要依赖脂肪酸氧化来提供能量。AMP 激活的蛋白激酶（AMPK）是大多数细胞中能量产生的关键调节剂，但 AMPK 在急性肾损伤肾小管上皮细胞中的功能尚不清楚。在这里，我们发现缺血/再灌注后体内和体外模型中 Thr172-AMPKα 的磷酸化迅速减少。肾小管上皮细胞特异性 AMPKα 缺失的小鼠在缺血/再灌注后表现出更严重的肾脏损伤和肾小管上皮细胞凋亡。AMPKα 缺失伴随着缺血/再灌注损伤后肾小管中脂质滴的积累以及神经酰胺和游离脂肪酸水平的升高。在机制上，缺血/再灌注触发神经酰胺的产生并激活蛋白磷酸酶 PP2A，使 Thr172-AMPKα 去磷酸化。AMPK 活性的降低抑制了丝氨酸/苏氨酸激酶 ULK1 介导的自噬，并阻碍了功能失调的线粒体的清除。通过别构 AMPK 激活剂 C24 靶向 PP2A-AMPK 轴，通过拮抗 PP2A 去磷酸化和促进线粒体自噬过程，在缺血/再灌注诱导的损伤期间恢复脂肪酸氧化并减少肾小管细胞凋亡。因此，我们的研究表明 AMPKα 在保护缺血/再灌注诱导的急性肾损伤中的肾小管上皮细胞损伤中起着重要作用。因此，激活 AMPK 可能是急性肾损伤治疗的一种潜在治疗策略。
