Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China,; Department of Medical Science, Yangzhou Polytechnic College, Yangzhou, China.
Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China,; Department of Nephrology, Nanjing Second Hospital, Nanjing Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Nanjing, China.
Toxicol Lett. 2022 Aug 15;367:19-31. doi: 10.1016/j.toxlet.2022.06.006. Epub 2022 Jul 13.
Uremic cardiomyopathy (UCM) is a common complication in patients with chronic kidney disease (CKD) and an important risk factor for death. P-Cresyl sulfate (PCS) is a damaging factor in UCM, and Klotho is a protective factor. However, the molecular mechanisms of Klotho and PCS in UCM and the relationship between PCS and Klotho are unclear. In vitro, Klotho treatment inhibited PCS-induced cardiomyocyte hypertrophy and apoptosis by blocking mTOR phosphorylation and inhibiting DNA double-strand breaks (DSBs), respectively. Moreover, PCS increased SIRT6 protein ubiquitination and downregulated SIRT6 protein expression, while Klotho inhibited SIRT6 protein ubiquitination and upregulated SIRT6 protein expression. In a mouse model of 5/6 nephrectomy (5/6Nx)-induced UCM, the expression of Klotho in the kidney and serum was decreased, and the expression of SIRT6 protein in myocardial tissues was lower. PCS further reduced Klotho and SIRT6 expression, aggravated heart structure and function abnormalities, and increased myocardial cell apoptosis in UCM mice. Administration of Klotho protein inhibited the downregulation of SIRT6 protein expression and improved cardiac structure and function. Furthermore, serum PCS level was associated with the left ventricular mass (LVM) and left ventricular mass index (LVMI) in hemodialysis patients. In conclusion, the uremic toxin PCS injures cardiomyocytes via mTOR phosphorylation and DSBs, and Klotho antagonizes the damaging effects of PCS. Moreover, the SIRT6 protein plays an important role in UCM, and Klotho suppresses SIRT6 ubiquitination induced by PCS, further improves cardiac structure and function in UCM and exerts protective effects.
尿毒症性心肌病 (UCM) 是慢性肾脏病 (CKD) 患者的常见并发症，也是死亡的重要危险因素。对甲酚硫酸盐 (PCS) 是 UCM 的一种损伤因子，Klotho 是一种保护因子。然而，Klotho 和 PCS 在 UCM 中的分子机制以及 PCS 和 Klotho 之间的关系尚不清楚。在体外，Klotho 治疗通过阻断 mTOR 磷酸化和抑制 DNA 双链断裂 (DSB)，分别抑制 PCS 诱导的心肌细胞肥大和凋亡。此外，PCS 增加了 SIRT6 蛋白泛素化并下调了 SIRT6 蛋白表达，而 Klotho 抑制了 SIRT6 蛋白泛素化并上调了 SIRT6 蛋白表达。在 5/6 肾切除术 (5/6Nx) 诱导的 UCM 小鼠模型中，肾脏和血清中的 Klotho 表达降低，心肌组织中的 SIRT6 蛋白表达降低。PCS 进一步降低了 Klotho 和 SIRT6 的表达，加重了 UCM 小鼠的心脏结构和功能异常，并增加了心肌细胞凋亡。Klotho 蛋白的给药抑制了 SIRT6 蛋白表达的下调，并改善了心脏结构和功能。此外，血清 PCS 水平与血液透析患者的左心室质量 (LVM) 和左心室质量指数 (LVMI) 相关。总之，尿毒症毒素 PCS 通过 mTOR 磷酸化和 DSB 损伤心肌细胞，Klotho 拮抗 PCS 的损伤作用。此外，SIRT6 蛋白在 UCM 中发挥重要作用，Klotho 抑制 PCS 诱导的 SIRT6 泛素化，进一步改善 UCM 中的心脏结构和功能并发挥保护作用。
