Chronic kidney disease causes defects in signaling through the insulin receptor sub strate/phosphatidylinositol 3-kinase/Akt pathway: Implications for muscle atrophy
Chronic kidney disease causes defects in signaling through the insulin receptor sub strate/phosphatidylinositol 3-kinase/Akt pathway: Implications for muscle atrophy
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DOI：
10.1681/asn.2004100842
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发表时间：
2006-05-01
影响因子：
13.6
通讯作者：
Mitch, William E.
中科院分区：
文献类型：
--
作者：
Bailey, James L.;Zheng, Bin;Mitch, William E.
慢性肾病 (CKD) 的并发症包括对胰岛素/IGF-1 的反应减弱以及由于 caspase-3 和泛素蛋白酶体系统激活而导致的肌肉蛋白水解加速。实验上，当磷脂酰肌醇 3-激酶 (PI3-K) 活性受到抑制时，肌肉细胞中就会发生蛋白水解。在酸中毒、CKD 和配对喂养对照大鼠的肌肉中，在生理条件下以及对快速刺激该通路的胰岛素剂量的反应中，评估了通过胰岛素受体底物 (IRS)/PI3-K/Akt 通路的受体后信号传导。基础IRS-1相关的PI3-K活性被CKD抑制； IRS-2 相关的 PI3-K 活性增加。 CKD 肌肉中激活的 Akt 基础水平也较低，表明较高的 IRS-2 相关 PI3-K 活性并不能补偿 IRS-1 相关 PI3-K 活性的降低。胰岛素治疗克服了这种异常。肌肉中 IRS-1 相关 PI3-K 活性较低并不是由于 IRS-1 蛋白减少，而是由于 PI3-K p85 亚基蛋白含量较高，而 p110 催化亚基没有伴随增加，这为 IRS-1 相关 PI3-K 活性较低提供了可能的解释。消除 CKD 酸中毒部分纠正了基础 IRS-1 相关 PI3-K 活性的降低和肌肉中蛋白质降解。结论是，在 CKD 中，酸中毒和 PI3-K p85 亚基的增加是有助于抑制肌肉中 PI3-K 活性的机制，这会导致肌肉蛋白水解加速。
Complications of chronic kidney disease (CKD) include depressed responses to insulin/IGF-1 and accelerated muscle proteolysis as a result of activation of caspase-3 and the ubiquitin-proteasome system. Experimentally, proteolysis in muscle cells occurs when there is suppression of phosphatidylinositol 3-kinase (PI3-K) activity. Postreceptor signaling through the insulin receptor substrate (IRS)/PI3-K/Akt pathway was evaluated in muscles of acidotic, CKD and pair-fed control rats under physiologic conditions and in response to a dose of insulin that quickly stimulated the pathway. Basal IRS-1-associated PI3-K activity was suppressed by CKD; IRS-2-associated PI3-K activity was increased. The basal level of activated Akt in CKD muscles also was low, indicating that the higher IRS-2-associated PI3-K activity did not compensate for the reduced IRS-1-associated PI3-K activity. Insulin treatment overcame this abnormality. The low IRS-1-associated PI3-K activity in muscle was not due to a decrease in IRS-1 protein, but there was a higher amount of the PI3-K p85 subunit protein without a concomitant increase in the p110 catalytic subunit, offering a potential explanation for the lower IRS-1-associated PI3-K activity. Eliminating the acidosis of CKD partially corrected the decrease in basal IRS-1-associated PI3-K activity and protein degradation in muscle. It is concluded that in CKD, acidosis and an increase in the PI3-K p85 subunit are mechanisms that contribute to suppression of PI3-K activity in muscle, and this leads to accelerated muscle proteolysis.