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Article

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

1
Division of Nephrology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan
2
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
3
Graduate Institute of Aerospace and Undersea Medicine, Academy of Medicine, National Defense Medical Center, Taipei 114, Taiwan
4
Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
5
Renal Care Joint Foundation, New Taipei City 220, Taiwan
6
Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
7
School of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan
8
Division of Pathology, En-Chu-Kong Hospital, New Taipei City 237, Taiwan
9
School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
10
Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
11
Department of Biotechnology and Pharmaceutical, Yuanpei University, Hsinchu 300, Taiwan
12
Department of Biomedical Engineering, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
13
Department of Orthopaedic Surgery, En-Chu-Kong Hospital, New Taipei City 237, Taiwan
14
Department of Clinical Laboratory, En Chu Kong Hospital, New Taipei City 237, Taiwan
15
Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
16
Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Cathay General Hospital, Taipei 106, Taiwan
*
Author to whom correspondence should be addressed.
Received: 10 June 2020 / Revised: 17 July 2020 / Accepted: 23 July 2020 / Published: 24 July 2020
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. View Full-Text
Keywords: alkaline phosphatase; c-Jun N-terminal kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase; nuclear factor-κB; osteogenesis; p-Cresyl Sulfate; reactive oxygen species; Runt-related transcription factor 2; uremic vascular calcification alkaline phosphatase; c-Jun N-terminal kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase; nuclear factor-κB; osteogenesis; p-Cresyl Sulfate; reactive oxygen species; Runt-related transcription factor 2; uremic vascular calcification
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MDPI and ACS Style

Chang, J.-F.; Hsieh, C.-Y.; Liou, J.-C.; Liu, S.-H.; Hung, C.-F.; Lu, K.-C.; Lin, C.-C.; Wu, C.-C.; Ka, S.-M.; Wen, L.-L.; Wu, M.-S.; Zheng, C.-M.; Ko, W.-C. Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells. Toxins 2020, 12, 472. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080472

AMA Style

Chang J-F, Hsieh C-Y, Liou J-C, Liu S-H, Hung C-F, Lu K-C, Lin C-C, Wu C-C, Ka S-M, Wen L-L, Wu M-S, Zheng C-M, Ko W-C. Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells. Toxins. 2020; 12(8):472. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080472

Chicago/Turabian Style

Chang, Jia-Feng, Chih-Yu Hsieh, Jian-Chiun Liou, Shih-Hao Liu, Chi-Feng Hung, Kuo-Cheng Lu, Chih-Cheng Lin, Chang-Chin Wu, Shuk-Man Ka, Li-Li Wen, Mai-Szu Wu, Cai-Mei Zheng, and Wen-Chin Ko. 2020. "Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells" Toxins 12, no. 8: 472. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080472

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