Oxidative stress contributes to vascular calcification in patients with chronic kidney disease. (January 2020)

• Record Type: Journal Article
• Authors: Huang, Mei; Zheng, Li; Xu, Hui; Tang, Damu; Lin, Lizhen; Zhang, Jin; Li, Cuifang; Wang, Wei; Yuan, Qiongjing; Tao, Lijian; Ye, Zunlong
• Is Part Of: Journal of molecular and cellular cardiology. Volume 138(2020)
• Page Start: 256
• Page End: 268
• Publication Date: 2020-01
• Subjects: Vascular calcification -- Vascular smooth muscle cells -- Chronic kidney disease -- Osteoblastic transition; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.12.006
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: Vascular calcification (VC) develops in patients with chronic kidney disease (CKD). VC occurs in early CKD (ECKD) patients without an elevation in serum phosphorus. Oxidative stress (OS) in ECKD patients is causative factor of VC. Serum of ECKD patients induces calcium deposition in vascular smooth muscle cells. Inhibition of OS protects VSMCs from calcium deposition induced by patient serum.