Objective: To investigate the changes of insulin-like growth factor 1 (IGF-1) axis in chronic kidney disease (CKD) and its role in skeletal muscle atrophy. Methods: A total of 240 patients with CKD stage 1-5 (without dialysis treatment) were included between August 2016 and February 2017. Serum IGF-1 and IGF-1 binding protein-3 (IGFBP-3) were measured using chemiluminescence, and the influencing factors of serum IGF-1 and IGFBP-3 were analyzed. Besides, male Sprague-Dawley rats (200-250 g) were randomly assigned to the sham-operated control group (Control, n=15) and the 5/6 nephrectomy group (n=15) as CKD animal model. The expressions of local IGF-1 and IGF-1 receptor (IGF-1R) of skeletal muscles were evaluated at the level of transcription and protein by real-time PCR and Western blotting. Results: There was no significant correlation between changes of serum IGF-1 level and estimated glomerular filtration rate (eGFR) (r=-0.066, P=0.307). However, after multivariable adjustment, serum IGFBP-3 increased with decreasing of eGFR (r=-0.181, P=0.005) in adult CKD patients. In multivariate analysis, age, eGFR, serum cholesterol level and 24 h urinary protein quantification were independent factors of serum IGFBP-3 in patients with CKD (R2=0.243, P<0.001). Animal experiments showed that the expression of IGF-1 mRNA and protein decreased in skeletal muscles of CKD rats. Expressions of IGF-1R mRNA and protein were slightly reduced and phosphorylation of IGF-1R was severely impaired in skeletal muscles of CKD rats. Conclusions: IGF-1 levels seem to be independent of renal function, but IGFBP-3 levels increased with decreasing of eGFR, which may cause a low affinity of IGF-1 with IGF-1R in skeletal muscles. Low affinity of IGF-1 with IGF-1R, as well as the decreasing of IGF-1 synthesis could lead to disorders of IGF-1R phosphorylation, and thus cause atrophy of skeletal muscles.
目的： 探讨慢性肾脏病(CKD)中胰岛素样生长因子1(IGF－1)轴的变化及其在骨骼肌萎缩中的作用。 方法： 以2016年8月至2017年2月在上海市第一人民医院肾内科初次住院、尚未行透析治疗的CKD 1～5期患者为研究对象，符合纳入标准的患者共240例。通过横断面研究观察CKD患者血清游离IGF－1与胰岛素样生长因子结合蛋白3(IGFBP－3)的水平，分析其相关影响因素，探讨CKD对循环中IGF－1和IGFBP－3水平的影响。然后构建5/6肾切除CKD大鼠模型，观察骨骼肌局部IGF－1及IGF－1受体(IGF－1R)的表达水平，探讨其在骨骼肌萎缩中的作用。 结果： 未进入透析治疗的CKD 1～5期成年患者血清游离IGF－1水平变化与估算肾小球滤过率(eGFR)水平无明显相关性(r＝－0.066，P＝0.307)。偏相关分析显示调整年龄和性别后，血清IGFBP－3与eGFR水平呈负相关(r＝－0.181，P＝0.005)，多重线性回归分析显示，年龄、eGFR、血清胆固醇水平及24 h尿蛋白定量是CKD患者血清IGFBP－3水平的独立相关因素(R2＝0.243, P<0.001)。动物实验显示，CKD大鼠骨骼肌IGF－1及IGF－1R mRNA和蛋白表达减少，IGF－1R自体磷酸化水平明显下降。 结论： 肾功能下降对血清游离IGF－1水平无明显影响，血IGFBP－3水平随着eGFR下降有逐渐升高趋势，后者可能导致骨骼肌内IGF－1与IGF－1R的亲和力下降；同时CKD导致的骨骼肌IGF－1合成减少引起IGF－1R生物活性下降，进而参与骨骼肌萎缩。.
Keywords: Insulin-like growth factor 1; Insulin-like growth factor binding protein 3; Muscular atrophy; Renal insufficiency, chronic.