AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes
AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes
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DOI：
10.1074/jbc.m110.136796
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发表时间：
2010-11-26
影响因子：
4.8
通讯作者：
Abboud, Hanna E.
中科院分区：
文献类型：
--
作者：
Eid, Assaad A.;Ford, Bridget M.;Abboud, Hanna E.
糖尿病和高血糖（HG）会增加NADPH氧化酶衍生的活性氧的产生，并诱导肾小球上皮细胞（足细胞）凋亡。足细胞的缺失会导致蛋白尿，蛋白尿是肾脏疾病进展的一个主要危险因素。在此，我们发现HG使AMP活化蛋白激酶（AMPK）失活，上调Nox4，增强NADPH氧化酶活性，并诱导足细胞凋亡。AMPK的激活可阻断HG诱导的Nox4表达、NADPH氧化酶活性以及凋亡。我们还确定了肿瘤抑制蛋白p53是HG暴露细胞中足细胞凋亡的一个介导因子。HG使AMPK失活会上调p53的表达和磷酸化，并且p53在Nox4的下游起作用。为了研究体内足细胞凋亡的机制，我们使用了OVE26小鼠，这是一种1型糖尿病模型。从这些小鼠分离出的肾小球显示AMPK磷酸化降低，Nox4和p53表达增强。在OVE26小鼠中用5 - 氨基咪唑 - 4 - 甲酰胺 - 1 - β - D - 呋喃核糖苷对AMPK进行药物激活可减弱Nox4和p53的表达。给予5 - 氨基咪唑 - 4 - 甲酰胺 - 1 - β - D - 呋喃核糖苷还可防止肾脏肥大、肾小球基底膜增厚、足突消失和足细胞丢失，从而显著减少蛋白尿。我们的研究结果揭示了AMPK的一种新功能，即整合对Nox4的代谢输入，并为p53激活诱导足细胞凋亡提供了新的见解。这些数据表明AMPK激活剂在阻断Nox4和活性氧产生以及减少1型糖尿病患者尿白蛋白排泄方面具有潜在的治疗用途。
Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes.