Division of Pediatric Nephrology, Rady Children's Hospital, University of California, San Diego, 9500 Gilman Drive, MC 0831, La Jolla, CA, 92093-0831, USA.
Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Sci Rep. 2021 Jul 23;11(1):15141. doi: 10.1038/s41598-021-94565-y.
Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β/CKD, Il6/CKD and Tnfα/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β/CKD mice but were only partially rescued in Il6/CKD and Tnfα/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg/kg/day, IP) or saline for 6 weeks and compared with WT/Sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra decreased serum and muscle expression of IL-6, TNF-α and IL-1β in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.
细胞因子，如白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β），引发炎症级联反应，可能在慢性肾脏病（CKD）相关恶病质的发病机制中发挥作用。CKD 通过 5/6 肾切除术在小鼠中诱导。我们研究了 Il1β/CKD、Il6/CKD 和 Tnfα/CKD 小鼠的能量稳态，并与野生型（WT）/CKD 对照组进行了比较。Il1β/CKD 小鼠的恶病质表型参数完全正常化，但 Il6/CKD 和 Tnfα/CKD 小鼠仅部分恢复。我们测试了 IL-1 受体拮抗剂 anakinra 对 CKD 相关恶病质的影响。WT/CKD 小鼠用 anakinra（2.5 mg/kg/天，IP）或生理盐水治疗 6 周，并与 WT/Sham 对照组进行比较。Anakinra 使 WT/CKD 小鼠的食物摄入量和体重增加、脂肪和瘦肉含量、代谢率和肌肉功能正常化，并减轻了 WT/CKD 小鼠脂肪组织和肌肉中能量稳态的分子扰动。Anakinra 降低了 WT/CKD 小鼠的血清和肌肉中 IL-6、TNF-α 和 IL-1β 的表达。Anakinra 减弱了 WT/CKD 小鼠白色脂肪组织的褐色化。此外，anakinra 使 WT/CKD 小鼠的腓肠肌重量和纤维大小正常化，并减轻了肌肉脂肪浸润。这伴随着纠正增加的肌肉消耗信号通路，同时促进 WT/CKD 小鼠腓肠肌中减少的成肌过程。我们对之前通过 RNAseq 分析在 WT/CKD 小鼠与对照组之间鉴定的前 20 个差异表达肌肉基因进行了 qPCR 分析。重要的是，17 个差异表达的肌肉基因在 anakinra 治疗的 WT/CKD 小鼠中减弱。总之，IL-1 受体拮抗可能代表一种针对 CKD 中脂肪组织褐色化和肌肉消耗的新型靶向治疗方法。
