Mizoribine Suppresses the Progression of Experimental Peritoneal Fibrosis in a Rat ModelTakahashi S.a · Taniguchi Y.c · Nakashima A.b · Arakawa T.a · Kawai T.a · Doi S.a · Ito T.d · Masaki T.b · Kohno N.a · Yorioka N.b
Departments of aMolecular and Internal Medicine and bAdvanced Nephrology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, cDivision of Clinical Pharmacotherapeutics, Department of Pharmaceutical Science, Hiroshima International University, Kure, and dSection of Nephrology, Department of Internal Medicine, Shimane University Faculty of Medicine, Shimane, Japan
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Background/Aims: Peritoneal fibrosis is a serious complication of peritoneal dialysis (PD). It has been reported that administration of mizoribine, an effective immunosuppressant, ameliorated renal fibrosis in a rat model of unilateral ureteral obstruction. We therefore examined the effects of mizoribine in an experimental model of peritoneal fibrosis. Methods: 24 rats were given a daily intraperitoneal injection of chlorhexidine gluconate and ethanol dissolved in saline. The rats were divided into three groups (n = 8 per group) that received either vehicle or mizoribine at a dose of 2 or 8 mg/kg once a day. 28 days after the start of the treatments the rats were sacrificed and peritoneal tissue samples collected. Macrophage infiltration (ED1), myofibroblast accumulation (α-smooth muscle actin (SMA)) and expression of type III collagen, transforming growth factor (TGF)-β and monocyte chemotactic protein-1 (MCP-1) were examined by immunohistochemistry. Results: Mizoribine significantly suppressed submesothelial zone thickening and reduced macrophage infiltration. Mizoribine also reduced collagen III+ area and decreased the number of α-SMA+, TGF-β+ and MCP-1+ cells. The magnitude of the changes observed was dose-dependent. Conclusion: The administration of mizoribine prevented the progression of peritoneal fibrosis in this rat model. Mizoribine may represent a novel therapy for peritoneal sclerosis in patients undergoing long-term PD.
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- Selgas R, Fernandez-Reyes MJ, Bosque E, Bajo MA, Borrego F, Jimenez C, Del Peso G, De Alvaro F: Functional longevity of the human peritoneum: how long is continuous peritoneal dialysis possible? Results of a prospective medium long-term study. Am J Kidney Dis 1994;23:64–73.
- Davies SJ, Bryan J, Phillips L, Russell GI: Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis and peritonitis. Nephrol Dial Transplant 1996;11:498–506.
- Ito T, Yorioka N: Peritoneal damage by peritoneal dialysis solutions. Clin Exp Nephrol 2008;12:243–249.
- Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, Mackenzie RK, Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13:470–479.
- Gandhi VC, Humayun HM, Ing TS, Daugirdas JT, Jablokow VR, Iwatsuki S, Geis WP, Hano JE: Sclerotic thickening of the peritoneal membrane in maintenance peritoneal dialysis patients. Arch Intern Med 1980;140:1201–1203.
Kawanishi H, Moriishi M: Encapsulating peritoneal sclerosis: prevention and treatment. Perit Dial Int 2007;27(suppl 2):S289–S292.
- Suga H, Teraoka S, Ota K, Komemushi S, Furutani S, Yamauchi S, Margolin S: Preventive effect of pirfenidone against experimental sclerosing peritonitis on rats. Exp Toxicol Pathol 1995;47:287–291.
- Mishima Y, Miyazaki M, Abe K, Ozono Y, Shioshita K, Xia Z, Harada T, Taguchi T, Koji T, Kohno S: Enhanced expression of heat shock protein 47 in rat model of peritoneal fibrosis. Perit Dial Int 2003;23:14–22.
- Koyama H, Tsuji M: Genetic and biochemical studies on the activation and cytotoxic mechanism of bredinin, a potent inhibitor of purine biosynthesis in mammalian cells. Biochem Pharmacol 1983;32:3547–3553.
- Kusumi T, Tsuda M, Katsunuma T, Yamamura M: Dual inhibitory effect of bredinin. Cell Biochem Funct 1989;7:201–204.
- Ishikawa H: Mizoribine and mycophenolate mofetil. Curr Med Chem 1999;6:575–597.
- Akiyama T, Okazaki H, Takahashi K, Hasegawa A, Tanabe K, Uchida K, Takahara S, Toma H: Mizoribine in combination therapy with tacrolimus for living donor renal transplantation: analysis of a nationwide study in Japan. Transplant Proc 2005;37:843–845.
- Tanaka E, Inoue E, Kawaguchi Y, Tomatsu T, Yamanaka H, Hara M, Kamatani N: Acceptability and usefulness of mizoribine in the management of rheumatoid arthritis in methotrexate-refractory patients and elderly patients, based on analysis of data from a large-scale observational cohort study. Mod Rheumatol 2006;16:214–219.
- Nakayamada S, Saito K, Umehara H, Ogawa N, Sumida T, Ito S, Minota S, Nara H, Kondo H, Okada J, Mimori T, Yoshifuji H, Sano H, Hashimoto N, Sugai S, Tanaka Y: Efficacy and safety of mizoribine for the treatment of Sjögren’s syndrome: a multicenter open-label clinical trial. Mod Rheumatol 2007;17:464–469.
- Tanaka H, Tsugawa K, Tsuruga K, Suzuki K, Nakahata T, Ito E, Waga S: Mizoribine for the treatment of lupus nephritis in children and adolescents. Clin Nephrol 2004;62:412–417.
- Honda M: Nephrotic syndrome and mizoribine in children. Pediatr Int 2002;44:210–216.
- Sakai T, Kawamura T, Shirasawa T: Mizoribine improves renal tubulointerstitial fibrosis in unilateral ureteral obstruction-treated rat by inhibiting the infiltration of macrophages and the expression of α-smooth muscle actin. J Urol 1997;158:2316–2322.
- Sato N, Shiraiwa K, Kai K, Watanabe A, Ogawa S, Kobayashi Y, Yamagishi-Imai H, Utsunomiya Y, Mitarai T: Mizoribine ameliorates the tubulointerstitial fibrosis of obstructive nephropathy. Nephron 2001;89:177–185.
- Nishino T, Miyazaki M, Abe K, Furusu A, Mishima Y, Harada T, Ozono Y, Koji T, Kohno S: Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress peritoneal fibrosis in rats. Kidney Int 2003;64:887–896.
- Yoshio Y, Miyazaki M, Abe K, Nishino T, Furusu A, Mizuta Y, Harada T, Ozono Y, Koji T, Kohno S: TNP-470, an angiogenesis inhibitor, suppresses the progression of peritoneal fibrosis in mouse experimental model. Kidney Int 2004;66:1677–1685.
- Doi S, Masaki T, Arakawa T, Takahashi S, Kawai T, Nakashima A, Naito T, Kohno N, Yorioka N: Protective effects of peroxisome proliferator-activated receptor γ ligand on apoptosis and hepatocyte growth factor induction in renal ischemia-reperfusion injury. Transplantation 2007;84:207–213.
- Hirai T, Masaki T, Kuratsune M, Yorioka N, Kohno N: PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell proliferation involving STAT3 activation. Clin Exp Immunol 2006;144:353–361.
- Hosotsubo H, Takahara S, Taenaka N: Simplified high-performance liquid chromatographic method for determination of mizoribine in human serum. J Chromatography 1988;432:340–345
- Kikuchi Y, Imakiire T, Yamada M, Saigusa T, Hyodo T, Hyodo N, Suzuki S, Miura S: Mizoribine reduces renal injury and macrophage infiltration in non-insulin-dependent diabetic rats. Nephrol Dial Transplant 2005;20:1573–1581.
- Vaage J, Lindblad WJ: Production of collagen type I by mouse peritoneal macrophages. J Leukoc Biol 1990;48:274–280.
- Nathan CF: Secretory products of macrophages. J Clin Invest 1987;79:319–326.
- Diamond JR, Kees-Folts D, Ding G, Frye JE, Restrepo NC: Macrophages, monocyte chemoattractant peptide-1, and TGF-β1 in experimental hydronephrosis. Am J Physiol 1994;266:F926–F933.
- Margetts PJ, Bonniaud P, Liu L, Hoff CM, Holmes CJ, West-Mays JA, Kelly MM: Transient overexpression of TGF-β1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 2005;16:425–436.
- Yang AH, Chen JY, Lin JK: Myofibroblastic conversion of mesothelial cells. Kidney Int 2003;63:1530–1539.
- Stypinski D, Obaidi M, Combs M, Weber M, Stewart AJ, Ishikawa H: Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers. Br J Clin Pharmacol 2007;63:459–468.
- Tanaka H, Tsugawa K, Nakahata T, Kudo M, Suzuki K, Ito E: Implication of the peak serum level of mizoribine for control of the serum anti-dsDNA antibody titer in patients with lupus nephritis. Clin Nephrol 2005;63:417–422.
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