Skip to main content

Advertisement

SpringerLink
Log in

Effect of sirolimus on the regression of peritoneal sclerosis in an experimental rat model

  • Nephrology – Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

Immunosuppressive and anti-inflammatory agents have recently become increasingly popular in the treatment of encapsulating peritoneal sclerosis (EPS). The aim of our study was to investigate the effects of sirolimus on EPS in a rat model.

Methods

We separated 32 non-uremic rats into four groups: 1 control group, 2 ml isotonic saline injected IP daily for 3 weeks; 2 chlorhexidine gluconate (CG) group, 2 ml 0,1 % CG and 15 % ethanol dissolved in saline injected IP daily for 3 weeks; 3 resting group, CG (weeks 0–3) plus peritoneal rest (weeks 3–6); 4 sirolimus group, CG (weeks 0–3), plus 0.2 ml (1 mg/ml) sirolimus (weeks 3–6). Pathological samples were examined by using hematoxylin eosin (HE) and Masson’s trichrome stains. Peritoneal thickness, fibrosis, vascular changes, and inflammation were evaluated by light microscopy. Finally, tissue metalloproteinase (MMP)-2 levels were measured by enzyme-linked immunoassay.

Results

In the CG group, there was a significant increase in peritoneal thickness, inflammatory activity, and fibrosis score compared to the control group (p < 0.05). We also observed a lower fibrosis score and less peritoneal thickening in the sirolimus group compared to the resting and CG groups (p < 0.05). There was no difference in histopathologic findings, except for the inflammatory activity in the sirolimus group, compared to the control group. Although the CG group had higher tissue MMP-2 levels than the control group, the tissue MMP-2 levels were not significantly different from the other groups.

Conclusions

Sirolimus has a beneficial effect on peritoneal fibrosis induced by CG. This suggests that sirolimus may have therapeutic value in the management of EPS.

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

Similar content being viewed by others

References

  1. Krediet RT (2007) 30 years of peritoneal dialysis development: the past and the future. Perit Dial Int 27:35–41

    Google Scholar 

  2. Hirahara I, Inoue M, Okuda K, Ando Y, Muto S, Kusano E (2007) The potential of matrix metalloproteinase–2 as a marker of peritoneal injury increased solute transport, or progression to encapsulating peritoneal sclerosis during peritoneal dialysis—a multicentre study in Japan. Nephrol Dial Transplant 22:560–567

    Article  PubMed  CAS  Google Scholar 

  3. Goodlad C, Brown EA (2011) Encapsulating peritoneal sclerosis: what have we learned? Semin Nephrol 31:183–198

    Article  PubMed  Google Scholar 

  4. Bozkurt D, Sipahi S, Cetin P et al (2009) Does immunosuppressive treatment ameliorate morphology changes in encapsulating peritoneal sclerosis? Perit Dial Int 29:206–210

    Google Scholar 

  5. Ro Y, Hamada C, Inaba M, Io H, Kaneko K, Tomino Y (2007) Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats. Nephrol Dial Transplant 22:2838–2848

    Article  PubMed  CAS  Google Scholar 

  6. Morath C, Arns W, Schwenger V et al (2007) Sirolimus in renal transplantation. Nephrol Dial Transplant 22:61–65

    Google Scholar 

  7. Guba M, von Breitenbuch P, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135

    Article  PubMed  CAS  Google Scholar 

  8. Rangan GK, Coombes JD (2007) Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis. Nephrol Dial Transplant 22:2175–2182

    Article  PubMed  CAS  Google Scholar 

  9. Damião MJ, Bertocchi AP, Monteiro RM et al (2007) The effects of rapamycin in the progression of renal fibrosis. Transplant Proc 39:457–459

    Article  PubMed  Google Scholar 

  10. Neef M, Ledermann M, Saegesser H, Schneider V, Reichen J (2006) Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol 45:786–796

    Article  PubMed  CAS  Google Scholar 

  11. Simler NR, Howell DC, Marshall RP et al (2002) The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur Respir J 19:1124–1127

    Article  PubMed  CAS  Google Scholar 

  12. Wong CF (2006) Clinical experience with tamoxifen in encapsulating peritoneal sclerosis. Perit Dial Int 26:183–184

    PubMed  Google Scholar 

  13. Wong CF, Beshir S, Khalil A, Pai P, Ahmad R (2005) Successful treatment of encapsulating peritoneal sclerosis with azathioprine and prednisolone. Perit Dial Int 25:285–287

    PubMed  Google Scholar 

  14. Ishii Y, Sawada T, Shimizu A et al (2001) An experimental sclerosing encapsulating peritonitis model in mice. Nephrol Dial Transplant 16:1262–1266

    Article  PubMed  CAS  Google Scholar 

  15. Williams JD, Craig KJ, Topley N et al (2002) Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 13:470–479

    PubMed  Google Scholar 

  16. Hawinkels LJAC, Verspaget HW, van Duijn W et al (2007) Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients. Br J Cancer 97:398–404

    Article  PubMed  CAS  Google Scholar 

  17. Kawanishi H, Watanabe H, Moriishi M, Tsuchiya S (2005) Successful surgical management of encapsulating peritoneal sclerosis. Perit Dial Int 25:39–47

    Google Scholar 

  18. Duman S, Bozkurt D, Sipahi S et al (2008) Effects of everolimus as an antiproliferative agent on regression of encapsulating peritoneal sclerosis in a rat model. Adv Perit Dial 24:104–110

    PubMed  CAS  Google Scholar 

  19. Winbanks CE, Grimwood L, Gasser A, Darby IA, Hewitson TD, Becker GJ (2007) Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation. Int J Biochem Cell Biol 39:206–219

    Article  PubMed  CAS  Google Scholar 

  20. Schmidt DW, Flessner MF (2008) Pathogenesis and treatment of encapsulating peritoneal sclerosis: basic and translational research. Perit Dial Int 28:10–15

    Google Scholar 

  21. Waller JR, Bicknell GR, Nicholson ML (2002) Sirolimus attenuates the expression of metalloproteinase-2 and -9 and inhibits intimal hyperplasia following balloon angioplasty. Transplant Proc 34:2881–2883

    Article  PubMed  CAS  Google Scholar 

  22. Khanna A, Plummer M, Bromberek C, Bresnahan B, Hariharan S (2002) Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity. Kidney Int 62:2257–2263

    Article  PubMed  CAS  Google Scholar 

  23. Kawanishi H, Kawaguchi Y, Fukui H et al (2004) Encapsulating peritoneal sclerosis in Japan: a prospective, controlled, multicenter study. Am J Kidney Dis 44:729–737

    PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Nephrology, Ankara Education and Research Hospital, Ankara, Turkey

    Mevlut Ceri, Selman Unverdi, Gulay Kocak & Murat Duranay

  2. Department of Pathology, Etlik Ihtisas Education and Research Hospital, Ankara, Turkey

    Mehmet Dogan & Hatice Unverdi

  3. Department of Nephrology, Gülhane Military Medical Academy, Istanbul, Turkey

    Ilhan Kurultak

  4. Department of Biochemistry, Faculty of Medicine, Karaelmas University, Zonguldak, Turkey

    Murat Can

  5. Nefroloji Klinigi, S.B. Ankara Egitim ve Arastirma Hastanesi, Cebeci, Ankara, Turkey

    Mevlut Ceri

  6. Department of Surgery, Ankara Education and Research Hospital, Ankara, Turkey

    Gokhan Karaca

  7. Department of Gastroenterology, Ankara Education and Research Hospital, Ankara, Turkey

    Erdem Akbal

Authors
  1. Mevlut Ceri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Selman Unverdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehmet Dogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hatice Unverdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gokhan Karaca
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gulay Kocak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ilhan Kurultak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Erdem Akbal
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Murat Can
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Murat Duranay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mevlut Ceri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ceri, M., Unverdi, S., Dogan, M. et al. Effect of sirolimus on the regression of peritoneal sclerosis in an experimental rat model. Int Urol Nephrol 44, 977–982 (2012). https://doi.org/10.1007/s11255-012-0167-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-012-0167-3

Keywords

Search

Navigation