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CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations

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Abstract

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, CD45-positive/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-β1), pro-α1 chain of Col1 (COL1A1), and CCL2.

Results

Stimulation of CD45+/Col1+ cells with high glucose concentrations increased the mRNA and protein levels of TGF-β1 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-β1, pro-COL1A1 and CCL2 and migration of the cells, and this effect was partly inhibited by treatment with CCR2 inhibitors.

Conclusion

These results suggest that CD45+/Col1+ cells may be directly involved, in part through CCL2/CCR2 signaling, in the fibrotic process under diabetic conditions.

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Acknowledgments

This study was supported by grants from the Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation (JST); Takeda Science Foundation; the Ministry of Education, Science, Sports, and Culture; and Diabetic Nephropathy Research from the Ministry of Health, Labor and Welfare of Japan.

Conflict of interest

The authors have declared that no conflict of interest exists.

Author information

Authors and Affiliations

  1. Department of Disease Control and Homeostasis, Kanazawa University, Kanazawa, Japan

    Akinori Hara, Norihiko Sakai, Kengo Furuichi & Shuichi Kaneko

  2. 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

    Takashi Wada

  3. Department of Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan

    Yoshio Sakai

  4. Department of Physiology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

    Yoh Takuwa

  5. Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    Naofumi Mukaida

  6. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Motohiro Takeya

  7. Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    Richard Bucala

  8. Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Kouji Matsushima

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  1. Akinori Hara
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Correspondence to Takashi Wada.

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Hara, A., Sakai, N., Furuichi, K. et al. CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations. Clin Exp Nephrol 17, 793–804 (2013). https://doi.org/10.1007/s10157-013-0796-6

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  • DOI: https://doi.org/10.1007/s10157-013-0796-6

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