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

Abstract

BackgroundHypertension 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.MethodsA 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.ResultsBy 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.Conclusions5/6Nx 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.

Neural and central mechanisms of kidney fibrosis after relief of ureteral obstruction

“…Mean arterial pressure and heart rate in these mice were recorded simultaneously via a catheter in the carotid artery by telemetry using TA11PA-C10 probes (Data Sciences International, MN, USA). 34 …”

“…ATG7 or AMPKα knockout in cultured cells was generated using the CRISPR/Cas9 according to manufacturer’s instruction (Genechem, Shanghai, China). 34 Small guide RNAs (sgRNAs) targeted ATG7, CRTC1 or CERB were cloned into U6-sgRNA-EF1a-Cas9-FLAG-P2A-puro by Genechem. sgRNA sequences were listed in Table S2 .…”

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“…Renal insufficiency is one of the independent risk factors for cardiovascular events [1][2][3]. In the early stage of renal insufficiency, this is mainly manifested as a decrease in vasodilatory capacity and vascular elasticity [4]. As the disease progresses, decreased kidney function leads to increased deposition of minerals and glycation end products in the blood, which can stimulate cell proliferation and extracellular matrix remodeling of the blood vessel wall, ultimately leading to the development of arterial stiffness [5].…”

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