Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, China.
Department of Nephrology, People's Hospital of Haimen District, Nantong, China.
Phytother Res. 2022 Aug;36(8):3265-3275. doi: 10.1002/ptr.7499. Epub 2022 May 23.
Chronic kidney disease (CKD) is often associated with muscle atrophy. However, the underlying molecular mechanisms are still not well understood. Here, we treated 5/6-nephrectomized (5/6Nx) rats with resveratrol and found that this treatment greatly improves renal function as evidenced by reduced proteinuria and cystatin C. Moreover, resveratrol ameliorates renal fibrosis by reducing transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF). Meanwhile, muscle atrophy in these 5/6Nx rats was largely attenuated by resveratrol. Immunoprecipitation revealed that SIRT1 physically interacts with FoxO1 in muscle, and this interaction was weakened in 5/6Nx rats. As a consequence, acetylated FoxO1 was increased in muscle of 5/6Nx rats. The application of resveratrol markedly reverses this trend. These data point out that SIRT1 is a key factor for linking renal disease and muscle atrophy. Indeed, both renal dysfunction and muscle atrophy were further aggravated by 5/6Nx in Sirt1 mice. Taken together, our data indicate that SIRT1 plays a pivotal role in muscle atrophy in CKD, and FoxO1 might be a substrate of SIRT1 in this process. Furthermore, resveratrol, together with other agonists of SIRT1, may hold great therapeutic potentials for treating CKD and its related muscle atrophy.
慢性肾脏病（CKD）常伴有肌肉萎缩。然而，其潜在的分子机制仍不清楚。在这里，我们用白藜芦醇治疗 5/6 肾切除（5/6Nx）大鼠，发现这种治疗方法大大改善了肾功能，表现为蛋白尿和胱抑素 C 减少。此外，白藜芦醇通过减少转化生长因子β（TGF-β）和结缔组织生长因子（CTGF）来改善肾纤维化。同时，白藜芦醇在很大程度上减轻了 5/6Nx 大鼠的肌肉萎缩。免疫沉淀显示 SIRT1 在肌肉中与 FoxO1 发生物理相互作用，而这种相互作用在 5/6Nx 大鼠中减弱。结果，5/6Nx 大鼠肌肉中的乙酰化 FoxO1 增加。白藜芦醇的应用明显逆转了这一趋势。这些数据指出 SIRT1 是将肾脏疾病和肌肉萎缩联系起来的关键因素。事实上，在 Sirt1 小鼠中，5/6Nx 进一步加重了肾功能不全和肌肉萎缩。总之，我们的数据表明 SIRT1 在 CKD 中的肌肉萎缩中起关键作用，FoxO1 可能是这个过程中 SIRT1 的底物。此外，白藜芦醇和其他 SIRT1 的激动剂可能具有治疗 CKD 及其相关肌肉萎缩的巨大治疗潜力。
