Oxidative stress contributes to vascular calcification in patients with chronic kidney disease.

Abstract

Vascular calcification (VC) is a major cause of mortality in patients with chronic kidney disease (CKD). While elevations in serum phosphorus contribute to VC, we provide evidence here for a major role of oxidative stress (OS) in VC pathogenesis without an apparent increase in serum phosphorus in early CKD. In a rat model for stage 5 CKD (CKD5), we observed 1) robust increases of VC and OS, 2) significant reductions of smooth muscle 22 alpha (SM22α) and calponin, and 3) upregulations in Runt-related transcription factor 2 (RUNX2) and collagen I in vascular smooth muscle cells (VSMCs). Inhibition of OS using MnTMPyP dramatically reduced these events without normalization of hyperphosphatemia. In CKD5 patients with VC (n = 11) but not in those without VC (n = 13), OS was significantly elevated. While the serum levels of calcium and phosphate were not altered in the animal model for early stage CKD (ECKD), OS, VC, SM22α, calponin, RUNX2, collagen I and NADPH oxidase 1 (NOX1) in VSMCs were all significantly changed. More importantly, serum (5%) derived from patients with ECKD (n = 30) or CKD5 (n = 30) induced SM22α and calponin downregulation, and RUNX2, collagen I, NOX1 upregulation along with a robust elevation of OS and calcium deposition in primary rat VSMCs. These alterations were all reduced by MnTMPyP, ML171 (a NOX1 inhibitor), and U0126 (an inhibitor of Erk signaling). Collectively, we provide a comprehensive set of evidence supporting an important role of OS in promoting VC development in CKD patients (particularly in those with ECKD); this was at least in part through induction of osteoblastic transition in VSMCs which may involve the Erk singling. Our research thus suggests that reductions in OS may prevent VC in CKD patients.

• Authors: Mei Huang, Li Zheng, Hui Xu, Damu Tang, Lizhen Lin, Jin Zhang, Cuifang Li, Wei Wang, Qiongjing Yuan, Lijian Tao, Zunlong Ye
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 138 Pg. 256-268 (01 2020) ISSN: 1095-8584 [Electronic] England
• PMID: 31866376 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Phosphates
• Calcium

Topics

• Animals
• Calcium (blood)
• Cells, Cultured
• Humans
• MAP Kinase Signaling System
• Male
• Muscle, Smooth, Vascular (pathology)
• Myocytes, Smooth Muscle (pathology)
• Osteoblasts (metabolism, pathology)
• Oxidative Stress
• Phosphates (blood)
• Rats, Sprague-Dawley
• Renal Dialysis
• Renal Insufficiency, Chronic (blood, complications)
• Vascular Calcification (blood, etiology, pathology)