Damage of uremic myocardium by p-cresyl sulfate and the ameliorative effect of Klotho by regulating SIRT6 ubiquitination. (15th August 2022)

• Record Type: Journal Article
• Authors: Chen, Cheng; Xie, Caidie; Xiong, Yiqing; Wu, Hanzhang; Wu, Lin; Zhu, Jingfeng; Xing, Changying; Mao, Huijuan
• Is Part Of: Toxicology letters. Volume 367(2022)
• Page Start: 19
• Page End: 31
• Publication Date: 2022-08-15
• Subjects: Klotho -- P-cresyl sulfate -- Uremic cardiomyopathy -- SIRT6; CKD chronic kidney disease -- CVD cardiovascular disease -- DSBs DNA double-strand breaks -- ESKD end-stage kidney disease -- LVH left ventricular hypertrophy -- LVM left ventricular mass -- LVMI left ventricular mass index -- NRCMs neonatal rat cardiomyocytes -- PCS p-cresyl sulfate -- UCM uremic cardiomyopathy -- 5/6Nx 5/6 nephrectomy; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.06.006
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: 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. Highlights: PCS induces cardiomyocyte hypertrophy and apoptosis. Klotho relieves cardiac damage induced by PCS. The mechanism underlying Klotho protecting against PCS-induced cardiac injury is inhibition of SIRT6 ubiquitination.