Klotho protects against chronic kidney disease-associated atherosclerotic plaque vulnerability in

Abstract

Objective To explore the effects of chronic kidney disease (CKD) on the instability of atherosclerotic plaques and investigate the role of Klotho in this pathological process. Methods A total of 24 ApoE-/- mice (8 weeks old) were randomly divided into sham group, CKD group and CKD+Klotho group (n=8 in each group). Mouse model of CKD was established by 5/6 nephrectomy in the corresponding mice. Then, these mice were fed with high-fat diet for 12 weeks, and Klotho was supplemented intraperitoneally at 0.01 mg/kg, every other day to the mice from the CKD+Klotho group. HE staining and α-SMA immunofluorescence staining were performed to evaluate the effects of CKD and Klotho on the atherosclerotic plaque size and fibrous cap thickness. Cultured human vascular smooth muscle cells (VSMCs) were treated with the serum from CKD stage 5 patients or health individuals, in presence of Klotho protein. β-Gal staining and DCFH-DA probe were conducted to detect the proportion of senescent VSMCs and production of reactive oxygen species (ROS). Results The CKD group had significantly enlarged atherosclerotic plaque size, and decreased fibrous cap thickness (8.43±1.74 vs 21.21±2.27 μm, P < 0.01) when compared with the sham group. Supplement of Klotho could reverse these effects (P < 0.01). In vitro experiment showed that there were larger proportion of galactosidase positive cells and higher ROS level in the VSMCs treated with the serum form CKD patients (P < 0.01). However, pre-incubation of Klotho could alleviate theses effects (P < 0.01). Conclusion Senescence of VSMCs is an important reason for instability of atherosclerotic plaques caused by CKD, and Klotho plays a protective role in the process.

Keywords

• klotho
• chronic kidney disease
• plaque stability
• vascular smooth muscle cells
• cellular senescence