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Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension

  • Qianqian Bi
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Chao Wang
    Affiliations
    Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou, Zhejiang 310058, China
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  • Guo Cheng
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Ningting Chen
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Bo Wei
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Xiaoli Liu
    Affiliations
    Department of Neurology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Li Li
    Affiliations
    Department of Pharmacy, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310013, China
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  • Cheng Lu
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Jian He
    Affiliations
    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Yuancheng Weng
    Affiliations
    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Chunyou Yin
    Affiliations
    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Yunfan Lin
    Affiliations
    Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang 314400, China
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  • Shu Wan
    Affiliations
    Brain Center, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Li Zhao
    Affiliations
    Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang 310058, China
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  • Jiaxi Xu
    Affiliations
    Department of Physiology and Pathophysiology, Xi’an Jiaotong University Health Science Center, Xi’an, Shanxi 710061, China
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  • Yi Wang
    Affiliations
    Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Yan Gu
    Correspondence
    Corresponding author
    Affiliations
    Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou, Zhejiang 310058, China
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  • Xiao Z. Shen
    Correspondence
    Corresponding author
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Author Footnotes
    13 Lead contact
    Peng Shi
    Correspondence
    Corresponding author
    Footnotes
    13 Lead contact
    Affiliations
    Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China

    Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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  • Author Footnotes
    13 Lead contact

      Highlights

      • Microglia constitutively produce PDGFB at steady state
      • Microglia-derived PDGFB promotes Kv4.3 channel expression in neurons via PDGFRα
      • Disruption of the PDGFB-Kv4.3 pathway predisposes mice to develop hypertension
      • Central supplementation of exogenous PDGFB suppressed the pressor response

      Summary

      Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.

      Graphical abstract

      Keywords

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