背景:慢性肾脏病(CKD)中的骨骼肌萎缩导致生活质量下降,发病率和死亡率增加。我们已经获得证据表明,氧化应激在CKD相关肌肉萎缩的进展中是必不可少的。柴胡皂苷A和D,从柴胡中提取的两种新出现的抗氧化剂,减轻肌肉萎缩还有待进一步研究。目的探讨这两种成分对CKD并发肌肉萎缩的作用及机制。
方法:在这项研究中,使用地塞米松(Dex)管理的C2C12肌管在体内和体外使用5/6肾切除小鼠建立肌肉营养不良模型。
结果:RNA测序结果表明,暴露于Dex会影响抗氧化活性,C2C12细胞的催化活性和酶调节活性。根据KEGG的分析,检测到的最大数量的差异表达基因富集在PI3K/AKT途径中.在体内,柴胡皂苷A和D保持肾功能,横截面尺寸,纤维型成分和抗炎能力。这两种成分抑制了MuRF-1的表达,并增强了MyoD和肌营养不良蛋白的表达。此外,柴胡皂苷A和D通过增加抗氧化酶的活性来维持氧化还原平衡,同时抑制活性氧的过度积累。此外,柴胡皂苷A和D刺激CKD小鼠PI3K/AKT及其下游Nrf2通路。柴胡皂苷A和D对增加C2C12肌管内径的影响,减少氧化应激并增强p-AKT的表达,p-mTOR,p70S6K,在体外观察到Nrf2和HO-1蛋白。重要的是,我们证实通过抑制PI3K和敲除Nrf2可以显著逆转这些保护作用。
结论:总之,柴胡皂苷A和D通过PI3K/AKT/Nrf2途径减少氧化应激改善CKD诱导的肌肉萎缩。
BACKGROUND: Skeletal muscle atrophy in chronic kidney disease (CKD) leads to a decline in quality of life and increased risk of morbidity and mortality. We have obtained evidence that oxidative stress is essential in the progression of CKD-related muscle atrophy. Whether
Saikosaponin A and D, two emerging antioxidants extracted from Bupleurum chinense DC, alleviate muscle atrophy remains to be further studied. The purpose of this study was to investigate the effects and mechanisms of these two components on CKD complicated with muscle atrophy.
METHODS: In this research, muscle dystrophy model was established using 5/6 nephrectomized mice in vivo and in vitro with Dexamethasone (Dex)-managed C2C12 myotubes.
RESULTS: The results of RNA-sequencing showed that exposure to Dex affected the antioxidant activity, catalytic activity and enzyme regulator activity of C2C12 cells. According to KEGG analysis, the largest numbers of differentially expressed genes detected were enriched in the PI3K/AKT pathway. In vivo, Saikosaponin A and D remain renal function, cross-section size, fiber-type composition and anti-inflammatory ability. These two components suppressed the expression of MuRF-1 and enhanced the expression of MyoD and Dystrophin. In addition,
Saikosaponin A and D maintained redox balance by increasing the activities of antioxidant enzymes while inhibiting the excessive accumulation of reactive oxygen species. Furthermore,
Saikosaponin A and D stimulated PI3K/AKT and its downstream Nrf2 pathway in CKD mice. The effects of
Saikosaponin A and D on increasing the inner diameter of C2C12 myotube, reducing oxidative stress and enhancing expression of p-AKT, p-mTOR, p70S6K, Nrf2 and HO-1 proteins were observed in vitro. Importantly, we verified that these protective effects could be significantly reversed by inhibiting PI3K and knocking out Nrf2.
CONCLUSIONS: In summary,
Saikosaponin A and D improve CKD-induced muscle atrophy by reducing oxidative stress through the PI3K/AKT/Nrf2 pathway.