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High glucose promotes TGF-β1 production by inducing FOS expression in human peritoneal mesothelial cells

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Abstract

Background

High glucose (HG) induces production of transforming growth factor-beta1 (TGF-β1), but the mechanism remains elusive. The aim of this study was to determine the gene(s) involved in HG-induced TGF-β1 production in human peritoneal mesothelial cells (HPMCs).

Methods

Microarray analysis was performed following a 3-h preincubation of HPMCs in 4 or 0.1 % glucose medium. Transcriptional genes were selected using Gene Ontology analysis for biological processes, including regulation of transcription and DNA-dependent. The effects of small interfering RNA (siRNA) treatments on the up-regulation of TGF-β1 mRNA were assessed by quantitative real-time polymerase chain reaction (qPCR). Finally, enzyme-linked immunosorbent assay (ELISA) was performed to determine which gene(s) contribute to the production of TGF-β1 protein in the medium.

Results

Microarray analysis revealed that the expression of 51 genes increased by more than 3-fold. Gene ontology analysis identified 13 genes for further study. qPCR confirmed mRNA amplification for 9 of the 13 genes. Furthermore, HG-induced up-regulation of TGF-β1 mRNA was attenuated by the siRNA of 4 genes: MDS1 and EVI1 complex locus (MECOM), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), FBJ murine osteosarcoma viral oncogene homolog (FOS) and activating transcription factor 3 (ATF3). ELISA showed that siRNA treatment of FOS, but not MECOM, FOSB or ATF3, suppressed the increase of TGF-β1 protein in the medium.

Conclusions

FOS is a downstream effector of HG stimulation in HPMCs that contributes to TGF-β1 production, suggesting that blocking FOS expression may be a therapeutic target for peritoneal fibrosis.

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References

  1. Yung S, Chan TM. Intrinsic cells: mesothelial cells- central players in regulating inflammation and resolution. Perit Dial Int. 2009;29:S21–7.

    CAS  PubMed  Google Scholar 

  2. Fusshoeller A. Histomorphological and functional changes of the peritoneal membrane during long-term peritoneal dialysis. Pediatr Nephrol. 2008;23:19–25.

    Article  PubMed  Google Scholar 

  3. Lv ZM, Wang Q, Wan Q, et al. The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells. PLoS One. 2011;6:e22806.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Weigert C, Brodbeck K, Sawadogo M, et al. Upstream stimulatory factor (USF) proteins induce human TGF-β1 gene activation via the glucose-response element-1013/-1002 in mesangial cells: up-regulation of USF activity by the hexosamine biosynthetic pathway. J Biol Chem. 2004;279:15908–15.

    Article  CAS  PubMed  Google Scholar 

  5. Nagarajan RP, Chen F, Li W, et al. Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB. Biochem J. 2000;348:591–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Weigert C, Sauer U, Brodbeck K, et al. AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-β1 promoter in mesangial cells. J Am Soc Nephrol. 2000;11:2007–16.

    CAS  PubMed  Google Scholar 

  7. Stylianou E, Jenner LA, Davies M, et al. Isolation, culture and characterization of human peritoneal mesothelial cells. Kidney Int. 1990;37:1563–70.

    Article  CAS  PubMed  Google Scholar 

  8. Yokoyama Y, Masaki T, Kiribayashi K, et al. 15-Deoxy-Δ12, 14-prostaglandin J2 inhibits angiotensin II-induced fibronectin expression via hepatocyte growth factor induction in human peritoneal mesothelial cells. Ther Apher Dial. 2009;14:43–51.

    Article  Google Scholar 

  9. Takahashi S, Taniguchi Y, Nakashima A, et al. Mizoribine suppresses the progression of experimental peritoneal fibrosis in a rat model. Nephron Exp Nephrol. 2009;112:e59–69.

    Article  CAS  PubMed  Google Scholar 

  10. Capalbo G, Mueller-Kuller T, Koschmieder S, et al. Characterization of ZC3H15 as a potential TRAF-2-interacting protein implicated in the NFκB pathway and overexpressed in AML. Int J Oncol. 2013;43:246–54.

    CAS  PubMed  Google Scholar 

  11. Ha H, Lee HB. Effect of high glucose on peritoneal mesothelial cell biology. Perit Dial Int. 2000;20:S15–8.

    PubMed  Google Scholar 

  12. Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA. 2006;103:2653–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Lee HB, Yu MR, Song JS, et al. Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells. Kidney Int. 2004;65:1170–9.

    Article  CAS  PubMed  Google Scholar 

  14. Wei J, Shi Y, Hou Y, et al. Knockdown of thioredoxin-interacting protein ameliorates high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells. Cell Signal. 2013;25:2788–96.

    Article  CAS  PubMed  Google Scholar 

  15. Pardo VG, Boland R, de Boland AR. 1α,25(OH)2-Vitamin D3 stimulates intestinal cell p38 MAPK activity and increases c-Fos expression. Int J Biochem Cell Biol. 2006;38:1181–90.

    Article  PubMed  Google Scholar 

  16. Smith ER, Smedberg JL, Rula ME, et al. Disassociation of MAPK activation and c-Fos expression in F9 embryonic carcinoma cells following retinoic acid-induced endoderm differentiation. J Biol Chem. 2001;276:32094–100.

    Article  CAS  PubMed  Google Scholar 

  17. Katsutani M, Ito T, Masaki T, et al. Glucose-based PD solution, but not icodextrin-based PD solution, induces plasminogen activator inhibitor-1 and tissue-type plasminogen activator in human peritoneal mesothelial cells via ERK1/2. Ther Apher Dial. 2007;11:94–100.

    Article  CAS  PubMed  Google Scholar 

  18. Yokoyama K, Hiyama A, Arai F, et al. C-Fos regulation by the MAPK and PKC pathways in intervertebral disc cells. PLoS One. 2013;8:e73210.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Ha H, Yu MR, Lee HB. High glucose-induced PKC activation mediates TGF-β1 and fibronectin synthesis by peritoneal mesothelial cells. Kidney Int. 2001;59:463–70.

    Article  CAS  PubMed  Google Scholar 

  20. Winzen R, Kracht M, Ritter B, et al. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J. 1999;18:4969–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Liu G, Ding W, Liu X, et al. c-Fos is required for TGFβ1 production and the associated paracrine migratory effects of human colon carcinoma cells. Mol Carcinog. 2006;45:582–93.

    Article  CAS  PubMed  Google Scholar 

  22. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6.

    Article  CAS  PubMed  Google Scholar 

  23. Sherwood DR, Butler JA, Kramer JM, et al. FOS-1 promotes basement-membrane removal during anchor-cell invasion in C. elegans. Cell. 2005;121:951–62.

    Article  CAS  PubMed  Google Scholar 

  24. Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer. 2005;41:2449–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a scientific grant from Baxter, Rhyokuhukai, and by grants-in-aid for kidney failure and hemodialysis research from the Japanese Association of Dialysis Physicians.

Conflict of interest

My co-authors and I declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

    Keiko Kokoroishi, Ayumu Nakashima, Shigehiro Doi, Toshinori Ueno, Toshiki Doi, Yukio Yokoyama & Takao Masaki

  2. Department of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, 1-2-3 Kasumi Minami-Ku, Hiroshima, 734-8553, Japan

    Ayumu Nakashima

  3. Department of Dental and Medical Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Kiyomasa Honda & Yukio Kato

  4. Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan

    Masami Kanawa

  5. Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Nobuoki Kohno

  6. Department of Blood Purification, Hiroshima University Hospital, 1-2-3 Kasumi Minami-Ku, Hiroshima, 734-8553, Japan

    Shigehiro Doi

Authors
  1. Keiko Kokoroishi
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  2. Ayumu Nakashima
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  3. Shigehiro Doi
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  4. Toshinori Ueno
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  6. Yukio Yokoyama
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  7. Kiyomasa Honda
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  8. Masami Kanawa
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  9. Yukio Kato
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  10. Nobuoki Kohno
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  11. Takao Masaki
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Corresponding authors

Correspondence to Ayumu Nakashima or Shigehiro Doi.

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Kokoroishi, K., Nakashima, A., Doi, S. et al. High glucose promotes TGF-β1 production by inducing FOS expression in human peritoneal mesothelial cells. Clin Exp Nephrol 20, 30–38 (2016). https://doi.org/10.1007/s10157-015-1128-9

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  • DOI: https://doi.org/10.1007/s10157-015-1128-9

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