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

Jia Feng Chang, 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, Wen Chin Ko

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number472
JournalToxins
Volume12
Issue number8
DOIs
Publication statusPublished - Jul 24 2020

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

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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