title: Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications.
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 (β2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, β2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective β2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced β-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The β2AR agonists enhanced β-arrestin2 and its interaction with IκBα, leading to downregulation of NF-κB. A siRNA specific for β-arrestin2 reversed β2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a β2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, β2AR agonists might have protective effects against diabetic renal and cardiovascular complications.
authors.affiliation: Department of Internal Medicine, Soon Chun Hyang University, Seoul, Korea; Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea; Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: nohneph@schmc.ac.kr.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Noh
authors.affiliation: Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Yu
authors.affiliation: Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Soon Chun Hyang University, Seoul, Korea.
authors.forename: Byoung-Won
authors.initials: BW
authors.lastname: Park
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: I-Hsien
authors.initials: IH
authors.lastname: Wu
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Motonobu
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: george.king@joslin.harvard.edu.
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D000074084:THP-1 Cells; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism
chemical_list: C553443:ADRB2 protein, human; C000605254:ARRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000893:Anti-Inflammatory Agents; C000605257:Arrb2 protein, rat; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; D000072000:NF-KappaB Inhibitor alpha; D013311:Streptozocin; D011493:Protein Kinase C
keywords: diabetes; fibrosis; inflammation; macrophages