Title CCL 2 / CCR 2 augments the production of transforming growth factor-beta 1 , type 1 collagen and CCL 2 by human CD 45-/ collagen 1-positive cells under high glucose concentrations

Background The migration and activation of circulating profibrotic cells including fibrocytes by the action of the chemokine/chemokine receptor system has been implicated in pathological fibrogenesis. In the present study, the involvement of collagen 1 (Col1)-producing cells, CD45positive/collagen-1-positive (CD45/Col1) cells originally named as fibrocytes via CC chemokine receptor 2 (CCR2), a cognate receptor of CCL2/monocyte chemoattractant protein, was examined in diabetic conditions. Methods Human CD45/Col1 cells originating from the peripheral blood of healthy volunteers were incubated with high concentrations of D-glucose or D-mannitol as an osmotic control for 12, 24 or 48 h. In addition, these cells were preincubated with CCL2 under high glucose concentrations. We also examined the effects of the inhibitors of glucose transporters (GLUTs), reactive oxygen species or CCR2 on the expression of transforming growth factor beta1 (TGF-b1), pro-a1 chain of Col1 (COL1A1), and CCL2. Results Stimulation of CD45/Col1 cells with high glucose concentrations increased the mRNA and protein levels of TGF-b1 and CCL2 and those of pro-COL1A1, and this effect was mediated in part by increased osmolality. Preincubation of the cells with cytochalasin B (a GLUT inhibitor) or N-acetylcysteine (an antioxidant) blocked the stimulatory effect of high glucose concentrations on these profibrotic molecules. In addition, preincubation of the cells with CCL2 enhanced the high glucose-induced upregulation of TGF-b1, pro-COL1A1 and CCL2 and migration of the cells, and this effect was partly inhibited by treatment with CCR2 inhibitors. A. Hara N. Sakai K. Furuichi S. Kaneko Department of Disease Control and Homeostasis, Kanazawa University, Kanazawa, Japan Y. Sakai Department of Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan M. Takeya Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan R. Bucala Department of Medicine, Yale University School of Medicine, New Haven, CT, USA N. Mukaida Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan Y. Takuwa Department of Physiology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan K. Matsushima Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan T. Wada (&) Division of Nephrology, Department of Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan e-mail: twada@m-kanazawa.jp 123 Clin Exp Nephrol (2013) 17:793–804 DOI 10.1007/s10157-013-0796-6

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