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Scavenging Intracellular ROS Attenuates p -Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells

Authors
  • Chang, Jia-Feng1, 2, 3
  • Hsieh, Chih-Yu2, 3,
  • Liou, Jian-Chiun
  • Liu, Shih-Hao
  • Hung, Chi-Feng
  • Lu, Kuo-Cheng
  • Lin, Chih-Cheng
  • Wu, Chang-Chin4
  • Ka, Shuk-Man
  • Wen, Li-Li
  • Wu, Mai-Szu3, 5
  • Zheng, Cai-Mei3, 5
  • Ko, Wen-Chin6
  • 1 Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
  • 2 Renal Care Joint Foundation, New Taipei City 220, Taiwan
  • 3 (C.-M.Z.)
  • 4 Department of Orthopaedic Surgery, En-Chu-Kong Hospital, New Taipei City 237, Taiwan
  • 5 Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
  • 6 Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Cathay General Hospital, Taipei 106, Taiwan
Type
Published Article
Journal
Toxins
Publisher
MDPI AG
Publication Date
Jul 24, 2020
Volume
12
Issue
8
Identifiers
DOI: 10.3390/toxins12080472
PMID: 32722241
PMCID: PMC7472002
Source
PubMed Central
Keywords
License
Green

Abstract

Osteogenesis in human arterial smooth muscle cell (HASMC) is a key feature of uremic vascular calcification (UVC). Concerning pro-oxidant properties of p -cresyl sulfate (PCS), the therapeutic effect of reactive oxygen species (ROS) scavenger on PCS triggered inflammatory signaling transduction in osteogenesis was investigated in this translational research. Based on severity level of chronic kidney disease (CKD), arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, oxidative injury and osteogenesis along with PCS concentrations. To mimic human UVC, HASMC model was used to explore whether PCS-induced ROS could trigger mitogen-activated protein kinase (MAPK) pathways with nuclear factor-κB (NF-κB) translocation that drive context-specific gene/protein expression, including Runt-related transcription factor 2 ( Runx2 ) and alkaline phosphatase (ALP). In parallel with PCS accumulation, CKD arteries corresponded with UVC severity, oxidative DNA damage (8-hydroxy-2′-deoxyguanosine), Runx2 and ALP. PCS directly phosphorylated extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/P38 (pERK/pJNK/pP38) and modulated NF-κB translocation to promote expressions of Runx2 and ALP in HASMC. Notably, intracellular ROS scavenger attenuated pERK signaling cascade and downstream osteogenic differentiation. Collectively, our data demonstrate PCS induces osteogenesis through triggering intracellular ROS, pERK/pJNK/pP38 MAPK pathways and NF-κB translocation to drive Runx2 and ALP expressions, culminating in UVC. Beyond mineral dysregulation, osteocytic conversion in HASMC could be the stimulation of PCS. Thus PCS may act as a pro-osteogenic and pro-calcific toxin. From the perspective of translational medicine, PCS and intracellular ROS could serve as potential therapeutic targets for UVC in CKD patients.

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