AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation
AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation
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DOI：
10.1152/ajprenal.00034.2011
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发表时间：
2011-12-01
影响因子：
4.2
通讯作者：
Levine, Jerrold S.
中科院分区：
文献类型：
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作者：
Lieberthal, Wilfred;Zhang, Leiqing;Levine, Jerrold S.
Lieberthal W，Zhang L，Patel VA，Levine JS. AMPK通过ATP非依赖性机制保护近端肾小管细胞免受应激诱导的凋亡：Akt激活的潜在作用美国肾脏生理学杂志301：F1177-F1192，2011年。首次发表于2011年9月28日; doi：10.1152/ajprenal.00034.2011.-我们研究了AMP激活蛋白激酶（AMPK）在调节培养的肾近端小管细胞的活力中的作用，这些细胞受到由葡萄糖剥夺、糖酵解抑制或线粒体呼吸抑制引起的代谢应激。我们使用BU.MPT细胞，一种条件永生化的肾上皮细胞系，来源于携带猿猴病毒40大肿瘤抗原温度敏感突变的转基因小鼠近端小管。所有三种形式的代谢应激都增加了AMPK的磷酸化和活性。AMPK的激活导致AMPK的两个下游靶标乙酰辅酶A羧化酶和p70 S6激酶磷酸化的变化。AMPK的抑制，无论是与化合物C（CC）或基因沉默，显着增加细胞凋亡的数量在所有三种形式的代谢应激反应。虽然细胞凋亡的数量与ATP耗竭的严重程度直接相关，但AMPK的抑制对细胞ATP水平没有影响。值得注意的是，代谢应激增加Akt的磷酸化和活性。此外，AMPK的抑制，CC或基因沉默，废除代谢应激激活Akt的能力。抑制AMPK诱导的细胞凋亡增加与抑制Akt诱导的细胞凋亡增加相当。我们的结论是急性代谢应激后AMPK的激活在促进培养的近端肾小管细胞的活力中起着重要作用。AMPK的保护作用似乎不是由于AMPK介导的细胞能量储存的保护，而是至少部分地由于AMPK介导的Akt活化。
Lieberthal W, Zhang L, Patel VA, Levine JS. AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation. Am J Physiol Renal Physiol 301: F1177-F1192, 2011. First published September 28, 2011; doi: 10.1152/ajprenal.00034.2011.-We examined the role of AMP-activated protein kinase (AMPK) in modulating the viability of cultured kidney proximal tubular cells subjected to metabolic stress induced by either dextrose deprivation, inhibition of glycolysis, or inhibition of mitochondrial respiration. We used BU.MPT cells, a conditionally immortalized kidney epithelial cell line derived from the proximal tubules of transgenic mice bearing a temperature-sensitive mutation of the simian virus 40 large-tumor antigen. All three forms of metabolic stress increased the phosphorylation and activity of AMPK. Activation of AMPK led to changes in the phosphorylation of two downstream targets of AMPK, acetyl coenzyme A carboxylase and p70 S6 kinase. Inhibition of AMPK, either pharmacologically with compound C (CC) or by gene silencing, significantly increased the amount of apoptosis in response to all three forms of metabolic stress. Although the amount of apoptosis was directly related to the severity of ATP depletion, inhibition of AMPK had no effect on cellular ATP levels. Notably, metabolic stress increased the phosphorylation and activity of Akt. Furthermore, inhibition of AMPK, with CC or gene silencing, abrogated the ability of metabolic stress to activate Akt. The augmentation of apoptosis induced by inhibition of AMPK was comparable to that induced by inhibition of Akt. We conclude that activation of AMPK following acute metabolic stress plays a major role in promoting the viability of cultured proximal tubular cells. Protection by AMPK appears to be due not to AMPK-mediated conservation of cell energy stores, but rather, at least in part, to AMPK-mediated activation of Akt.