Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure
Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure
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DOI：
10.1172/jci37672
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Giardino, Ida
中科院分区：
文献类型：
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作者：
D'Apolito, Maria;Du, Xueliang;Giardino, Ida
虽然已知尿素的超生理浓度会增加培养细胞的氧化应激，但通常认为慢性肾衰竭患者尿素水平升高的毒性可以忽略不计。我们之前的研究表明，ROS增加了O-linked β - n -乙酰氨基葡萄糖（O-GlcNAc）对细胞内蛋白质的修饰，而其他研究表明，O-GlcNAc对胰岛素信号分子修饰的增加减少了胰岛素信号转导。由于在终末期肾病患者中观察到氧化应激和胰岛素抵抗，我们试图确定尿素在这些表型中的作用。用疾病相关浓度的尿素处理3T3-L1脂肪细胞诱导ROS产生，引起胰岛素抵抗，脂肪因子视黄醇结合蛋白4 （RBP4）和抵抗素的表达增加，o - glcnac修饰的胰岛素信号分子增加。对手术诱导肾衰竭小鼠模型（尿毒症小鼠）的研究显示，ROS生成增加，O-GlcNAc修饰胰岛素信号分子，内脏脂肪组织中RBP4和抵抗素的表达增加。尿毒症小鼠也表现出胰岛素抵抗和葡萄糖不耐受，用抗氧化剂SOD/过氧化氢酶模拟物治疗使这些缺陷正常化。超氧化物歧化酶/过氧化氢酶模拟处理也能阻止正常小鼠尿素输注后胰岛素抵抗的发生。这些数据表明，靶向治疗尿素诱导的活性氧可能有助于降低终末期肾脏疾病引起的高发病率和死亡率。
Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked beta-N-acetyl-glucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased expression of adipokines retinol binding protein 4 (RBP4) and resistin, and increased O-GlcNAc-modified insulin signaling molecules. Investigation of a mouse model of surgically induced renal failure (uremic mice) revealed increased ROS production, modification of insulin signaling molecules by O-GlcNAc, and increased expression of RBP4 and resistin in visceral adipose tissue. Uremic mice also displayed insulin resistance and glucose intolerance, and treatment with an antioxidant SOD/catalase mimetic normalized these defects. The SOD/catalase mimetic treatment also prevented the development of insulin resistance in normal mice after urea infusion. These data suggest that therapeutic targeting of urea-induced ROS may help reduce the high morbidity and mortality caused by end-stage renal disease.