Involvement of lysyl oxidase in the pathogenesis of arterial stiffness in chronic kidney disease

Abstract

Patients with chronic kidney disease (CKD) are at increased risk for adverse cardiovascular events. CKD is associated with increases in arterial stiffness while improvements of arterial stiffness, correlates with better survival. However, arterial stiffness is increased early in CKD suggesting there might be additional factors, unique to kidney disease, that increase arterial stiffness. Lysyl Oxidase (LOX) is a key mediator of collagen cross-linking and matrix remodeling. LOX is predominantly expressed in the cardiovascular system and its up regulation has been associated with increased tissue stiffening and extracellular matrix remodeling. Thus, the present study was designed to evaluate the role of increased LOX activity in inducing aortic stiffness in CKD and if β-aminopropionitrile (BAPN), a LOX inhibitor could prevent aortic stiffness by reducing collagen cross-linking. Eight-week-old male C57BL/6 mice were subjected to 5/6 nephrectomy (Nx) or Sham surgery. After surgery, mice were randomized to BAPN (300 mg/kg/day) or vehicle treatment for 4-weeks. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound. Aortic levels of LOX were assessed by ELISA and cross-linked, total collagen levels were analyzed by Mass spectrometry and Sircol assay respectively. Nx mice showed increased PWV, aortic wall remodeling compared to control mice. Collagen cross-linking was increased in parallel with the increases in total collagen in the aorta of Nx mice. In contrast, Nx mice that received BAPN treatment showed decreased cross-linked collagens and PWV compared to vehicle treatment. Our results indicated that LOX might be an early and key mediator of aortic stiffness in CKD.

Aging of the Arterial System

“…Chronic kidney disease may also impair collagen cross-linking and matrix remodeling. In this context, lysyl oxidase has recently been proposed by Sharma et al, as a cofactor for the development of increased arterial stiffness in mice with early impaired kidney function [ 66 ]. Authors demonstrated that mice treated with lysyl oxidase inhibitors showed a decrease in cross-linked collagens and PWV compared to vehicle treatment.…”