AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation
AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation
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DOI：
10.1152/ajpcell.00350.2007
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发表时间：
2008-01-01
影响因子：
5.5
通讯作者：
Vlassara, Helen
中科院分区：
文献类型：
--
作者：
Cai, Weijing;He, John Cijiang;Vlassara, Helen
晚期糖基化终产物（AGEs）可促进糖尿病和衰老相关疾病中活性氧（ROS）的形成和氧化应激（OS）。AGE诱导的OS被AGER 1抑制，AGER 1是一种AGE受体，其抵消晚期糖基化终产物受体（EGFR）和表皮生长因子受体（EGFR）介导的Shc/Ras信号激活，导致OS降低、Akt、FKHRL 1和抗氧化剂;例如，在一个实施例中，我们研究了两种确定的AGEs-羧甲基赖氨酸（CML）和甲基乙二醛衍生物（MG）对这些细胞通路的影响以及它们与人胚肾细胞（HEK 293）中AGER 1的功能关系。用任一AGE化合物刺激HEK 293细胞以氧化还原依赖性方式使Akt和FKHRL 1的磷酸化增加约3倍。p66 shc突变体的使用表明，AGE诱导的作用需要p66 shc的Ser-36磷酸化。AGE诱导的FKHRL 1磷酸化导致MnSOD下调70%，这种作用部分被磷脂酰肌醇3-激酶抑制剂（LY-294002）阻断，并被抗氧化剂（N-乙酰半胱氨酸）强烈抑制。这些促氧化反应在AGER 1过表达细胞中被抑制，并且当小干扰RNA（siRNA）降低AGER 1表达时再次出现。这些研究指出了AGEs诱导OS的新途径，包括FKHRL 1失活和MnSOD抑制，通过人肾细胞中p66 shc的Ser-36磷酸化。这代表了AGER 1维持细胞抵抗OS的关键机制。因此，在衰老和糖尿病中发现的AGER 1的减少可能进一步增强OS并降低先天抗氧化防御。
Advanced glycation end products (AGEs) promote reactive oxygen species (ROS) formation and oxidant stress (OS) in diabetes and aging-related diseases. AGE-induced OS is suppressed by AGER1, an AGE-receptor that counteracts receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR)mediated Shc/Ras signal activation, resulting in decreased OS. Akt, FKHRL1, and antioxidants; e. g., MnSOD, regulate OS. Serine phosphorylation of p66(shc) also promotes OS. We examined the effects of two defined AGEs Ne-carboxy-methyl-lysine (CML) and methylglyoxal derivatives (MG) on these cellular pathways and their functional relationship to AGER1 in human embryonic kidney cells (HEK293). Stimulation of HEK293 cells with either AGE compound increased phosphorylation of Akt and FKHRL1 by approximately threefold in a redox-dependent manner. The use of p66shc mutants showed that the AGE-induced effects required Ser-36 phosphorylation of p66shc. AGE-induced phosphorylation of FKHRL1 led to a 70% downregulation of MnSOD, an effect partially blocked by a phosphatidylinositol 3-kinase inhibitor (LY-294002) and strongly inhibited by an antioxidant (N-acetylcysteine). These pro-oxidant responses were suppressed in AGER1 overexpressing cells and reappeared when AGER1 expression was reduced by small interfering RNA (siRNA). These studies point to a new pathway for the induction of OS by AGEs involving FKHRL1 inactivation and MnSOD suppression via Ser-36 phosphorylation of p66shc in human kidney cells. This represents a key mechanism by which AGER1 maintains cellular resistance against OS. Thus the decrease of AGER1 noted in aging and diabetes may further enhance OS and reduce innate antioxidant defenses.