Inflammatory cytokines and reactive oxygen species as mediators of chronic kidney disease-related vascular calcification

Am J Hypertens. 2015 Jun;28(6):746-55. doi: 10.1093/ajh/hpu225. Epub 2014 Nov 27.

Abstract

Background: Vascular calcification, a regulated process in chronic kidney disease (CKD), requires vascular smooth muscle cell (VSMC) differentiation into osteoblast-like cells. This phenomenon can be enhanced by inflammatory cytokines and production of reactive oxygen species (ROS). In CKD rats with vascular calcification, we investigated whether inflammatory cytokines, ROS generation, and downstream signaling events are associated with CKD-related vascular calcification.

Methods: CKD was induced in male Wistar rats by renal mass ablation and vascular calcification was induced with a high calcium-phosphate diet and vitamin D supplementation (Ca/P/VitD). At week 3-6, hemodynamic parameters were determined and thoracic aorta was harvested for assessment of vascular calcification, macrophage infiltration, cytokines expression, VSMC differentiation, ROS generation, and related signaling pathway activation.

Results: CKD rats treated with Ca/P/VitD developed medial calcification of thoracic aorta and increased pulse pressure and aortic pulse wave velocity. VSMC differentiation was confirmed by increased bone morphogenetic protein-2 and osteocalcin expression and reduced α-smooth muscle actin expression. The expression of interleukin-1β, interleukin-6, and tumor necrosis factor were also increased. The expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) were increased, whereas the expression of antioxidant enzymes (SOD1, SOD2, Gpx1, and Prdx1) was reduced in CKD + Ca/P/VitD rats. Oxidized peroxiredoxin, a sensor of ROS generation, was significantly increased and ROS-sensitive signaling pathways were activated in the aorta from CKD + Ca/P/VitD rats.

Conclusion: This study demonstrates a relationship between inflammation/ROS and arterial calcification in CKD and contributes to understanding of the complex pathways that mediate arterial calcification in CKD patients.

Keywords: NADPH oxidase; blood pressure; chronic kidney disease; hypertension; inflammatory cytokines; reactive oxygen species; vascular calcification..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Disease Models, Animal
  • Glutathione Peroxidase / metabolism
  • Glutathione Peroxidase GPX1
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism
  • NADPH Oxidases / metabolism
  • Oxidative Stress
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism*
  • Renal Insufficiency, Chronic* / complications
  • Renal Insufficiency, Chronic* / metabolism
  • Signal Transduction
  • Superoxide Dismutase / metabolism
  • Vascular Calcification* / etiology
  • Vascular Calcification* / metabolism

Substances

  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Reactive Oxygen Species
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • NADPH Oxidases
  • Glutathione Peroxidase GPX1
  • Gpx1 protein, rat