2. Academic Validation
  3. Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension

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

  • Immunity. 2022 Aug 9;55(8):1466-1482.e9. doi: 10.1016/j.immuni.2022.06.018.
Qianqian Bi 1,  Chao Wang 2,  Guo Cheng 1,  Ningting Chen 1,  Bo Wei 1,  Xiaoli Liu 3,  Li Li 4,  Cheng Lu 1,  Jian He 5,  Yuancheng Weng 5,  Chunyou Yin 5,  Yunfan Lin 6,  Shu Wan 7,  Li Zhao 8,  Jiaxi Xu 9,  Yi Wang 10,  Yan Gu 11,  Xiao Z Shen 12,  Peng Shi 13
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Neurology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
  • 4 Department of Pharmacy, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310013, China.
  • 5 Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
  • 6 Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang 314400, China.
  • 7 Brain Center, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
  • 8 Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 9 Department of Physiology and Pathophysiology, Xi'an Jiaotong University Health Science Center, Xi'an, Shanxi 710061, China.
  • 10 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
  • 11 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. Electronic address: guyan2015@zju.edu.cn.
  • 12 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. Electronic address: shenx@zju.edu.cn.
  • 13 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. Electronic address: ship@zju.edu.cn.
PMID: 35863346 DOI: 10.1016/j.immuni.2022.06.018
Abstract

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.

Keywords

Kcnd3; Kv4.3; PDGFR inhibitor; hypertension; hypothalamic paraventricular nucleus; microglia; paracrine action; platelet-derived growth factor B; potassium current; sympathetic nerve activity.

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