Skip to main content

Advertisement

SpringerLink
Log in

Hepatocyte growth factor ameliorates methylglyoxal-induced peritoneal inflammation and fibrosis in mouse model

  • Original article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Background

Peritoneal dialysis (PD) is essential for patients with end-stage renal disease. Peritoneal fibrosis (PF) is a complex inflammatory, fibrogenic process. No effective treatments are available to prevent these processes. Hepatocyte growth factor (HGF) possesses anti-inflammatory and anti-fibrotic properties. The aim of this study was to analyze whether HGF suppresses MGO-induced peritoneal inflammation and fibrosis in a mouse model.

Methods

PF was induced by intraperitoneal (IP) injections of MGO for 14 days. C57/BL/6 mice were divided into three groups: Sham group (only vehicle); Sham + MGO group (PF induced by MGO); and HGF + MGO group (PF mice treated with recombinant human-HGF). PF was assessed from tissue samples by Masson’s trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry and quantitative real-time PCR.

Results

MGO-injected mice showed significant thickening of the submesothelial compact zone with PF. Treatment with HGF significantly reduced PM thickness and suppressed the expression of collagen I and III and α-SMA. Expression of profibrotic and proinflammatory cytokines (TGF-β, TNF-α, IL-1β) was reduced by HGF treatment. The number of macrophages, and M1 and M2 macrophage-related markers, such as CD86, CD206, and CD163, was reduced in HGF + MGO mice.

Conclusion

HGF attenuates MGO-induced PF in mice. Furthermore, HGF treatment reduces myofibroblast and macrophage infiltration, and attenuates the upregulated expression of proinflammatory and profibrotic genes in peritoneal tissues. HGF might be an effective approach to prevent the development of PF in patients undergoing PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Robinson BM, et al. Factors affecting outcomes in patients reaching end-stage kidney disease worldwide: differences in access to renal replacement therapy, modality use, and haemodialysis practices. Lancet. 2016;388:294–306.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Morgan LW, et al. Glucose degradation products (GDP) retard remesothelialization independently of D-glucose concentration. Kidney Int. 2003;64:1854–66.

    Article  CAS  PubMed  Google Scholar 

  3. Williams JD, et al. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol. 2002;13:470–9.

    Article  PubMed  Google Scholar 

  4. Witowski J, et al. Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal mesothelial cells. J Am Soc Nephrol. 2001;12:2434–41.

    Article  CAS  PubMed  Google Scholar 

  5. Margetts PJ, et al. Transient overexpression of TGF-β1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol. 2005;16:425–36.

    Article  CAS  PubMed  Google Scholar 

  6. Thomas AH, et al. Collagen fragments modulate innate immunity. Exp Biol Med (Maywood). 2007;232:406–11.

    CAS  Google Scholar 

  7. Epstein FH, et al. Transforming growth factor β in tissue fibrosis. N Engl J Med. 1994;331:1286–92.

    Article  Google Scholar 

  8. Padwal M, et al. Matrix metalloproteinase 9 is associated with peritoneal membrane solute transport and induces angiogenesis through β-catenin signaling. Nephrol Dial Transplant. 2017;32:50–61.

    CAS  PubMed  Google Scholar 

  9. Fielding CA, et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40:40–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou Q, et al. Preventing peritoneal membrane fibrosis in peritoneal dialysis patients. Kidney Int. 2016;90:515–24.

    Article  PubMed  Google Scholar 

  11. Li Q, et al. A pathogenetic role for M1 macrophages in peritoneal dialysis-associated fibrosis. Mol Immunol. 2018;94:131–9.

    Article  CAS  PubMed  Google Scholar 

  12. Nagai T, et al. Linagliptin ameliorates methylglyoxal-induced peritoneal fibrosis in mice. PLoS ONE. 2016;11:e0160993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kitamura M, et al. Epigallocatechin gallate suppresses peritoneal fibrosis in mice. Chem Biol Interact. 2012;195:95–104.

    Article  CAS  PubMed  Google Scholar 

  14. Hirahara I, et al. Methylglyoxal induces peritoneal thicking by mesenchymal-like mesothelial cells in rats. Nephrol Dial Transplant. 2009;24:437–47.

    Article  CAS  PubMed  Google Scholar 

  15. Nita I, et al. Hepatocyte growth factor secreted by bone marrow stem cell reduce ER stress and improves repair in alveolar epithelial II cells. Sci Rep. 2017;7:41901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Komaki Y, et al. Hepatocyte growth factor facilitates esophageal mucosal repair and inhibits the submucosal fibrosis in a rat model of esophageal ulcer. Digestion. 2019;99:227–38.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Z, et al. Antifibrotic effects of hepatocyte growth factor on endothelial-to-mesenchymal transition via transforming growth factor-betal(TGF-β1)/smad and Akt/mTOR/P70S6K signaling pathways. Ann Transplant. 2018;23:1–10.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rodgers JT, et al. HGFA is an injury-regulated systemic factor that induces the transition of stem cells into GAlert. Cell Rep. 2017;19:479–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yu MA, et al. HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium. J Am Soc Nephrol. 2009;20:567–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shinohara M, et al. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest. 1998;101:1142–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mizuno S, et al. HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. FASEB J. 2005. https://doi.org/10.1096/fj.04-1535fje.

    Article  PubMed  Google Scholar 

  22. Mizuno S, et al. Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int. 2001;59:1304–14.

    Article  CAS  PubMed  Google Scholar 

  23. Schievenbusch S, et al. Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts. Biochem Biophys Res Commun. 2009;385:55–61.

    Article  CAS  PubMed  Google Scholar 

  24. Chen YT, et al. Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury. J Am Soc Nephrol. 2014;25:2847–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang X, et al. Type I collagen or gelatin stimulates mouse peritoneal macrophages to aggregate and produce pro-inflammatory molecules through upregulated ROS levels. Int Immunopharmacol. 2019;76:105845.

    Article  CAS  PubMed  Google Scholar 

  26. Yang AH, et al. Myofibroblastic conversion of mesothelial cells. Kidney Int. 2003;63:1530–9.

    Article  PubMed  Google Scholar 

  27. Azuma J, et al. Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Ther. 2006;13:1206–13.

    Article  CAS  PubMed  Google Scholar 

  28. Yung S, et al. Impact of a low-glucose peritoneal dialysis regimen on fibrosis and inflammation biomarkers. Perit Dial Int. 2015;35:147–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Matsuoka T, et al. Hepatocyte growth factor prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis. J Nephrol. 2008;21:64–73.

    PubMed  Google Scholar 

  30. Ido A, et al. Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein. Hepatol Res. 2004;30:175–81.

    Article  CAS  PubMed  Google Scholar 

  31. Jiang D, et al. Protective action of hepatocyte growth factor on transforming growth factor β-1-induced α-smooth muscle actin and extracellular matrix in cultured human peritoneal fibroblasts. Case Reports Clin Pract Rev. 2010;16:250–4.

    Google Scholar 

  32. Lee HA, et al. Ethyl acetate extract from Asparagus cochinchinensis exerts anti-inflammatory effects in LPS-stimulated RAW264.7 macrophage cells by regulating COX-2/iNOS, inflammatory cytokine expression, MAP kinase pathways, the cell cycle and anti-oxidant activity. Mol Med Rep. 2017;15:1613–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kigerl KA, et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29:13435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wijesundera KK, et al. M1- and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide (TAA), focusing on Iba1 and galectin-3. Exp Mol Pathol. 2014;96:382–92.

    Article  CAS  PubMed  Google Scholar 

  35. Chen S, Lu Z, et al. Cathelicidin-WA polarizes E. coli K88-induced M1 macrophage to M2-like macrophage in RAW264.7 cells. Int Immunopharmacol. 2018;54:52–9.

    Article  CAS  PubMed  Google Scholar 

  36. Zhao Y, et al. Comparison of the characteristics of macrophages derived from murine spleen, peritoneal cavity, and bone marrow. J Zhejiang Univ Sci B. 2017;18:1055–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mlambo NC, et al. Increased levels of transforming growth factor beta 1 and basic fibroblast growth factor in patients on CAPD: a study during non-infected steady state and peritonitis. Inflammation. 1999;23:131–9.

    Article  CAS  PubMed  Google Scholar 

  38. Bellón T, et al. Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis. Nephrol Dial Transplant. 2011;26:2995–3005.

    Article  PubMed  CAS  Google Scholar 

  39. Beilmann M, Vande Woude GF, Dienes HP, Schirmacher P. Hepatocyte growth factor-stimulated invasiveness of monocytes. Blood. 2000;95:3964–9.

    Article  CAS  PubMed  Google Scholar 

  40. Jiang Q, et al. Differential responsiveness of cord and adult blood monocytes to hepatocyte growth factor. Clin Exp Immunol. 2001;125:222–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen Q, et al. Induction of met proto-oncogene (hepatocyte growth factor receptor) expression during human monocyte-macrophage differentiation. Cell Growth Differ. 1996;7:821–32.

    CAS  PubMed  Google Scholar 

  42. Galimi F, et al. Hepatocyte growth factor is a regulator of monocyte- macrophage function. J Immunol. 2001;166:1241–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan

    Haruhito Yoshimine, Shiroh Tanoue, Yutaro Ibi, Masato Minami, Mai Nakahara, Koki Tokunaga, Shuji Kanmura & Akio Ido

Authors
  1. Haruhito Yoshimine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiroh Tanoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yutaro Ibi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masato Minami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mai Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Koki Tokunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shuji Kanmura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akio Ido
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiroh Tanoue.

Ethics declarations

Conflict of interest

The authors have declared that no conflicts of interest exist.

Human and animal rights

All procedures performed in studies involving animals were in accordance with the Kagoshima University Animal Experiment Rules. This article does not contain any studies with human participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

10157_2021_2067_MOESM1_ESM.pptx

Experimental protocol of the animal model of peritoneal fibrosis and the administration of recombinant-hepatocyte growth factor (HGF). The mice were divided into three groups (n = 5 per group). Peritoneal fibrosis was induced by intraperitoneal injection of methylglyoxal (MGO) (40 mM) for 14 consecutive days (a). All mice were implanted with an osmotic pump subcutaneously on the back. The contents of the pump were saline or HGF (b). Body weight loss was attenuated by HGF (*p< 0.05 vs. Sham+MGO) (c) (PPTX 2828 KB)

10157_2021_2067_MOESM2_ESM.pptx

Serum hepatocyte growth factor (HGF) concentration and proliferation cell nuclear antigen (PCNA) expression in liver tissue of mice with peritoneal fibrosis. Comparison of concentrations of serum HGF released from intraperitoneal osmotic pump versus subcutaneous osmotic pump on day 7 (n = 3) (a). PCNA immunohistochemical analysis of liver tissue was performed to confirm HGF release from the osmotic pump (n = 5) (b) (*p < 0.01, **p < 0.05) (PPTX 436 KB)

10157_2021_2067_MOESM3_ESM.pptx

Expression of c-MET and phospho-c-MET in the peritoneal membrane of mice.c-MET and phospho-c-MET in the peritoneal membrane were compared by western blotting. β-actin was used as a loading control for western blot (n = 3) (PPTX 107 KB)

The oligonucleotide sequence for the real time RT-PCR (PPTX 36 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yoshimine, H., Tanoue, S., Ibi, Y. et al. Hepatocyte growth factor ameliorates methylglyoxal-induced peritoneal inflammation and fibrosis in mouse model. Clin Exp Nephrol 25, 935–943 (2021). https://doi.org/10.1007/s10157-021-02067-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-021-02067-y

Keywords

Search

Navigation