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Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications

Authors
Noh, HyunjinYu, Mi RaKim, Hyun JooLee, Ji HyePark, Byoung-WonWu, I-HsienMatsumoto, MotonobuKing, George L.
Issue Date
Jul-2017
Publisher
Elsevier Inc.
Keywords
diabetes; fibrosis; inflammation; macrophages
Citation
Kidney International, v.92, no.1, pp 101 - 113
Pages
13
Journal Title
Kidney International
Volume
92
Number
1
Start Page
101
End Page
113
URI
https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/7423
DOI
10.1016/j.kint.2017.02.013
ISSN
0085-2538
1523-1755
Abstract
Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2-adrenergic receptor (beta 2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-a production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, beta 2AR agonists inhibited diabetes-induced tumor necrosis factor-alpha production, which was prevented by co-treatment with a selective beta 2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced beta-arrestin2, a negative regulator of NF-kappa B activation, and its interaction with I kappa B alpha. This subsequently enhanced phosphorylation of I kappa B alpha and activation of NF-kappa B. The beta 2AR agonists enhanced beta-arrestin2 and its interaction with I kappa B alpha, leading to downregulation of NF-kappa B. A siRNA specific for beta-arrestin2 reversed beta 2AR agonist-mediated inhibition of NF-kappa B activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a beta 2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, beta 2AR agonists might have protective effects against diabetic renal and cardiovascular complications.
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