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

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.