The effects of tacrolimus and mycophenolate mofetil on regression of encapsulating peritoneal sclerosis in a rat model
Abstract
Objective: Encapsulating peritoneal sclerosis (EPS) is a rare, but potentially fatal complication of peritoneal dialysis. Currently, treatment of peritoneal fibrosis is not fully possible yet. In this study, we aimed to demonstrate the effects of tacrolimus therapy on peritoneal fibrosis and inflammation when administered alone or with mycophenolate mofetil (MMF) in the EPS model induced in rats. Methods: Thirty six Wistar albino rats were separated into six equal groups. Group I was the control group. Group II-VI were administered intraperitoneal chlorhexidine (CH) for induced EPS model in rats. Group II, IV, V, VI were administered isotonic liquid, tacrolimus, tacrolimus and concurrently with CH, tacrolimus and MMF together, respectively. Group III was not administered any drug. All peritoneal samples were stained immunohistochemically with matrix metalloproteinase-2 (MMP-2) antibody. Thickness of peritoneal fibrosis, subserosal large collagen fibers, subserosal fibroblast proliferation and subserosal fibrotic matrix deposition were evaluated. Results: Comparing the experimentally induced EPS groups, the best histopathological results and the largest staining with MMP-2 were achieved in Group VI. Furthermore, in all treatment groups (IV, V, VI) more staining with MMP-2 was detected compared to non-treatment groups (I, II, III) but no statistically significant differences were found among all groups. A statistically significant remission was observed in all histopathological parameters, primarily peritoneal thickness in rats that were administered MMF with tacrolimus, compared to rats which were administered tacrolimus only. Conclusion: Concurrent use of tacrolimus and MMF in the treatment of EPS may be a promising approach.
References
2) Hirahara I, Inoue M, Okuda K, Ando Y, Muto S, Kusano E. 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. 2007;22(2):560-7. doi: 10.1093/ndt/gfl566.
3) Hung KY, Huang JW, Tsai TJ, Hsieh BS. Peritoneal fibrosing syndrome: pathogenetic mechanism and current therapeutic strategies. J Chin Med Assoc. 2005;68(9):401-5. doi: 10.1016/S1726-4901(09)70154-6.
4) Martin J, Yung S, Robson RL, Steadman R, Davies M. Production and regulation of matrix metalloproteinases and their inhibitors by human peritoneal mesothelial cells. Perit Dial Int. 2000;20(5):524-33.
5) Fukudome K, Fujimoto S, Sato Y, Hisanaga S, Eto T. Peritonitis increases MMP-9 activity in peritoneal effluent from CAPD patients. Nephron. 2001;87(1):35-41. doi: 10.1159/000045882.
6) Nghiem P. "Topical immunomodulators?": introducing old friends and a new ally, tacrolimus. J Am Acad Dermatol. 2001;44(1):111-3. doi: 10.1067/mjd.2001.110902.
7) Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, Cejalvo D. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation. 1993;55(6):1265-72. doi: 10.1097/00007890-199306000-00011.
8) Anglicheau D, Legendre C, Beaune P, Thervet E. Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics. 2007;8(7):835-49. doi: 10.2217/14622416.8.7.835.
9) Nagano J, Iyonaga K, Kawamura K, Yamashita A, Ichiyasu H, Okamoto T, et al. Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis. Eur Respir J. 2006;27(3):460-9. doi: 10.1183/09031936.06.00070705.
10) Khanna A, Plummer M, Bromberek C, Bresnahan B, Hariharan S. Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity. Kidney Int. 2002;62(6):2257-63. doi: 10.1046/j.1523-1755.2002.00668.x.
11) Bicknell GR, Williams ST, Shaw JA, Pringle JH, Furness PN, Nicholson ML. Differential effects of cyclosporin and tacrolimus on the expression of fibrosis-associated genes in isolated glomeruli from renal transplants. Br J Surg. 2000;87(11):1569-75. doi: 10.1046/j.1365-2168.2000.01577.x.
12) Hur E, Bozkurt D, Timur O, Bicak S, Sarsik B, Akcicek F, et al. The effects of mycophenolate mofetil on encapsulated peritoneal sclerosis model in rats. Clin Nephrol. 2012;77(1):1-7. doi: 10.5414/cn107140.
13) Huddam B, Başaran M, Koçak G, Azak A, Yalçın F, Reyhan NH, et al. The use of mycophenolate mofetil in experimental encapsulating peritoneal sclerosis. Int Urol Nephrol. 2015;47(8):1423-8. doi: 10.1007/s11255-015-1015-z.
14) Lafrance JP, Létourneau I, Ouimet D, Bonnardeaux A, Leblanc M, Mathieu N, et al. Successful treatment of encapsulating peritoneal sclerosis with immunosuppressive therapy. Am J Kidney Dis. 2008;51(2):e7-10. doi: 10.1053/j.ajkd.2007.07.036.
15) Jiang S, Tang Q, Rong R, Tang L, Xu M, Lu J, et al. Mycophenolate mofetil inhibits macrophage infiltration and kidney fibrosis in long-term ischemia-reperfusion injury. Eur J Pharmacol. 2012;688(1-3):56-61. doi: 10.1016/j.ejphar.2012.05.001.
16) Ishii Y, Sawada T, Shimizu A, Tojimbara T, Nakajima I, Fuchinoue S, et al. An experimental sclerosing encapsulating peritonitis model in mice. Nephrol Dial Transplant. 2001;16(6):1262-6. doi: 10.1093/ndt/16.6.1262.
17) Fieren MW, Betjes MG, Korte MR, Boer WH. Posttransplant encapsulating peritoneal sclerosis: a worrying new trend? Perit Dial Int. 2007;27(6):619-24.
18) Korte MR, Habib SM, Lingsma H, Weimar W, Betjes MG. Posttransplantation encapsulating peritoneal sclerosis contributes significantly to mortality after kidney transplantation. Am J Transplant. 2011;11(3):599-605. doi: 10.1111/j.1600-6143.2010.03434.x.
19) Waller JR, Brook NR, Bicknell GR, Nicholson ML. Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia. Transpl Int. 2004;17(1):9-14. doi: 10.1007/s00147-003-0653-8.
20) Gregory CR, Pratt RE, Huie P, Shorthouse R, Dzau VJ, Billingham ME, et al. Effects of treatment with cyclosporine, FK 506, rapamycin, mycophenolic acid, or deoxyspergualin on vascular muscle proliferation in vitro and in vivo. Transplant Proc. 1993;25(1 Pt 1):770-1.
21) Roos N, Poulalhon N, Farge D, Madelaine I, Mauviel A, Verrecchia F. In vitro evidence for a direct antifibrotic role of the immunosuppressive drug mycophenolate mofetil. J Pharmacol Exp Ther. 2007;321(2):583-9. doi: 10.1124/jpet.106.117051.
22) Badid C, Vincent M, McGregor B, Melin M, Hadj-Aissa A, Veysseyre C, et al. Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney. Kidney Int. 2000;58(1):51-61. doi: 10.1046/j.1523-1755.2000.00140.x.
23) Manojlovic Z, Blackmon J, Stefanovic B. Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. PLoS One. 2013;8(6):e65897. doi: 10.1371/journal.pone.006589.
24) Waller JR, Murphy GJ, Bicknell GR, Toomey D, Nicholson ML. Effects of the combination of rapamycin with tacrolimus or cyclosporin on experimental intimal hyperplasia. Br J Surg. 2002;89(11):1390-5. doi: 10.1046/j.1365-2168.2002.02271.x.
25) Luo L, Sun Z, Wu W, Luo G. Mycophenolate mofetil and FK506 have different effects on kidney allograft fibrosis in rats that underwent chronic allograft nephropathy. BMC Nephrol. 2012;13:53. doi: 10.1186/1471-2369-13-53.
26) Doller A, Akool el-S, Müller R, Gutwein P, Kurowski C, Pfeilschifter J, et al. Molecular mechanisms of cyclosporin A inhibition of the cytokine-induced matrix metalloproteinase-9 in glomerular mesangial cells. J Am Soc Nephrol. 2007;18(2):581-92. doi: 10.1681/ASN.2006060568.
27) Gagliano N, Moscheni C, Dellavia C, Stabellini G, Ferrario VF, Gioia M. Immunosuppression and gingival overgrowth: gene and protein expression profiles of collagen turnover in FK506-treated human gingival fibroblasts. J Clin Periodontol. 2005;32(2):167-73. doi: 10.1111/j.1600-051X.2005.00654.x.
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