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Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction

Wei Cao, Liling Wu, Xiaodong Zhang, Jing Zhou, Jian Wang, Zhichen Yang, Huanjuan Su, Youhua Liu, Christopher S. Wilcox and Fan Fan Hou
JASN October 2020, 31 (10) 2312-2325; DOI: https://doi.org/10.1681/ASN.2020030234
Wei Cao
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Liling Wu
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Xiaodong Zhang
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Jing Zhou
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Jian Wang
2State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
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Zhichen Yang
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Huanjuan Su
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Youhua Liu
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Christopher S. Wilcox
3Division of Nephrology and Hypertension, Georgetown University Medical Central, Washington, DC
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Fan Fan Hou
1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, People’s Republic of China
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Significance Statement

Vascular smooth muscle cells (VSMCs) of resistance arteries receive sympathetic nerve signals, and subsequently elicit an endothelium-dependent anticontractile response to modulate vasoconstriction, but the specific role of this neurovascular transmission in hypertension in CKD is unknown. In this investigation, in vivo, ex vivo, and in vitro models were used to study neurovascular transmission and its contribution to elevated vascular resistance in CKD, independent of vascular structural changes. The experiments revealed that the impaired anticontractile component of neurovascular transmission relies on sustained enhancement of sympathetic discharge, which is sensed at VSMCs and impairs expression of connexin 43 in gap junctions at myoendothelial junctions. This cascade interrupts endothelium-dependent hyperpolarizing responses and increases vascular tone. The findings provide new insights into the development of hypertension in CKD.

Abstract

Background Hypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)–dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown.

Methods A mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance.

Results By 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice.

Conclusions 5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.

  • chronic kidney disease
  • hypertension
  • neurovascular transmission
  • sympathetic nervous system
  • connexin 43
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (10)
Journal of the American Society of Nephrology
Vol. 31, Issue 10
October 2020
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Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction
Wei Cao, Liling Wu, Xiaodong Zhang, Jing Zhou, Jian Wang, Zhichen Yang, Huanjuan Su, Youhua Liu, Christopher S. Wilcox, Fan Fan Hou
JASN Oct 2020, 31 (10) 2312-2325; DOI: 10.1681/ASN.2020030234

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Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction
Wei Cao, Liling Wu, Xiaodong Zhang, Jing Zhou, Jian Wang, Zhichen Yang, Huanjuan Su, Youhua Liu, Christopher S. Wilcox, Fan Fan Hou
JASN Oct 2020, 31 (10) 2312-2325; DOI: 10.1681/ASN.2020030234
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Keywords

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  • neurovascular transmission
  • sympathetic nervous system
  • connexin 43

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