Mizoribine has been shown to possess an immunosuppressive action that inhibits the proliferation of lymphocytes selectively by interfering with inosine monophosphate dehydrogenase. Recent studies have demonstrated that mizoribine improves renal tubulointerstitial fibrosis in the rat model of unilateral ureteral obstruction (UUO) by inhibiting the infiltration of macrophages. We, therefore, examined the dose dependency of the suppressive effect of mizoribine on the infiltration of interstitial macrophages and T lymphocytes and the interstitial volume in UUO-treated kidneys. Furthermore, we investigated the expression of osteopontin (OPN), known to be a chemoattractant protein for macrophages, in the renal cortex. In rats with UUO, the interstitial volume was markedly expanded, and macrophage and T lymphocyte infiltration in the interstitium and the expression of OPN in the cortical tubules were greatly increased. Treatment with mizoribine ameliorated the increase in interstitial volume induced by UUO. Interstitial infiltration of macrophages and T lymphocytes was dose dependently suppressed by mizoribine, and the decreased macrophage infiltration was correlated with inhibition of tubular OPN expression. These results suggest that mizoribine has a beneficial effect on several steps contributing to the progression of tubulointerstitial fibrosis caused by obstruction of the ureter.

1.
Kuncio GS, Neilson EG, Haverty T: Mechanisms of tubulointerstitial fibrosis. Kidney Int 1991;39:550–556.
2.
Striker GE, Schainuck LI, Cutler RE, Benditt EP: Structural-functional correlations in renal disease. I. A method for assaying and classifying histopathologic changes in renal disease. Hum Pathol 1970;1:615–630.
3.
Schainuk LI, Striker GE, Cutler RE, Benditt EP: Structural-functional correlations in renal disease. II. The correlations. Hum Pathol 1970;1:631–641.
4.
Klahr S: New insights into the consequences and mechanisms of renal impairment in obstructive nephropathy. Am J Kidney Dis 1991;18:689–699.
5.
Sharma AK, Mauer SM, Kim Y, Michael AF: Interstitial fibrosis in obstructive nephropathy. Kidney Int 1993;44:774–788.
6.
Diamond JR, Ricardo SD, Klahr S: Mechanisms of interstitial fibrosis in obstructive nephropathy. Semin Nephrol 1998;18:594–602.
7.
Giachelli CM, Pichler R, Lombardi D, Denhardt DT, Alpers CE, Schwartz SM, Johnson RJ: Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. Kidney Int 1994;45:515–524.
8.
Pichler R, Giachelli CM, Lombardi D, Pippin J, Gordon K, Alpers CE, Schwartz SM, Johnson RJ: Tubulointerstitial disease in glomerulonephritis: Potential role of osteopontin (uropontin). Am J Pathol 1994;144:915–926.
9.
Mizuno K, Tsujino M, Takada M, Hayashi M, Atsumi K, Asano K, Matsuda T: Studies on bredinin. I. Isolation, characterization and biological properties. J Antibiot (Tokyo) 1974;27:775–782.
10.
Amemiya H, Suzuki S, Niiya S, Watanabe H, Kotake T: Synergistic effect of cyclosporine and mizoribine on survival of dog renal allografts. Transplantation 1988;46:768–771.
11.
Gregory CR, Gourley IM, Cain GR, Broaddus TW, Cowgill LD, Willits NH, Patz JD, Ishizaki G: Effects of combination cyclosporine/mizoribine immunosuppression on canine renal allograft recipients. Transplantation 1988;45:856–859.
12.
Gregory CR, Gourley IM, Haskins SC, Cain GR, Ishizaki G, Cowgill LD, Willits NH, Patz JD: Effects of mizoribine on canine renal allograft recipients. Am J Vet Res 1988;49:305–311.
13.
Osakabe T, Uchida H, Masaki Y, Yokota K, Sato K, Nakayama Y, Ohkubo M, Kumano K, Endo T, Watanabe K, Aso K: Studies on immunosuppression with low-dose cyclosporine combined with mizoribine in experimental and clinical cadaveric renal allotransplantation. Transplant Proc 1989;21:1598–1600.
14.
Kusaba R, Otubo O, Sugimoto H, Takahashi I, Yamada Y, Yamauchi J, Akiyama N, Inou T: Immunosuppressive effect of bredinin in the management of patients with renal transplantation. Proc Eur Dial Transplant Assoc 1981;18:420–425.
15.
Tajima A, Hata M, Ohta N, Ohtawara Y, Suzuki K, Aso Y: Bredinin treatment in clinical kidney allografting. Transplantation 1984;38:116–118.
16.
Amemiya H, Suzuki S, Watanabe H, Hayashi R, Niiya S: Synergistically enhanced immunosuppressive effect by combined use of cyclosporine and mizoribine. Transplant Proc 1989;21:956–958.
17.
Ishikawa H: Mizoribine and mycophenolate mofetil. Curr Med Chem 1999;6:575–597.
18.
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.
19.
Turka LA, Dayton J, Sinclair G, Thompson CB, Mitchell BS: Guanine ribonucleotide depletion inhibits T cell activation. J Clin Invest 1991;87:940–948.
20.
Hirohata S, Yanagida T: Inhibition of expression of cyclin A in human B cells by an immunosuppressant mizoribine. J Immunol 1995;155:5175–5183.
21.
Sakai T, Kawamura T, Shirasawa T: Mizoribine improves renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-treated rat by inhibiting the infiltration of macrophages and the expression of alpha smooth muscle actin. J Urol 1997;158:2316–2322.
22.
Nikolic-Paterson DJ, Lan HY, Hill PA, Atkins RC: Macrophages in renal injury. Kidney Int 1994;45(suppl):79–82.
23.
Vaage J, Lindblad WJ: Production of collagen type I by mouse peritoneal macrophages. J Leukoc Biol 1990;48:274–280.
24.
Nathan CF: Secretory products of macrophages. J Clin Invest 1987;79:319–326.
25.
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.
26.
Eddy AA: Protein restriction reduces transforming growth factor-β and interstitial fibrosis in nephrotic syndrome. Am J Physiol 1994;266:F884–F893.
27.
Eddy AA: Expression of genes that promote renal interstitial fibrosis in rats with proteinuria. Kidney Int 1996,49(suppl):49–54.
28.
Klahr S, Morrissey JJ: Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring. Kidney Int 1997;52(suppl):111–114.
29.
Ishidoya S, Morrissey J, McCracken R, Reyes A, Klahr S: Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 1995;47:1285–1294.
30.
Wang Y, Chen J, Chen L, Tay YC, Rangan GK, Harris DCH: Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol 1997;8:1537–1545.
31.
Zoja C, Donadelli R, Colleoni S, Figliuzzi M, Bonazzola S, Morigi M, Remuzzi G: Protein overload stimulates RANTES production by proximal tubular cells depending on NF-κ-B activation. Kidney Int 1998;53:1608–1615.
32.
Ricardo SD, Levinson ME, DeJoseph MR, Diamond JR: Expression of adhesion molecules in rat renal cortex during experimental hydronephrosis. Kidney Int 1996;50:2002–2010.
33.
Romero F, Rodriguez-Iturbe B, Parra G, Gonzalez L, Herrera-Acosta J, Tapia E: Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999;55:945–955.
34.
Müller V, Hamar P, Szabo A, Knust E, Vogelsang M, Heemann U: Effect of mycophenolate mofetil on the in vivo infiltration of lymphocytes in the rat remnant kidney. Transplant Proc 1998;30:982.
35.
Struz F, Müller GA: On the progression of chronic renal disease. Nephron 1995;69:371–379.
36.
Shappell SB, Gurpinar T, Lechago J, Suki WN, Truong LD: Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: Lymphocyte infiltration is not required for progressive tubulointerstitial injury. J Am Soc Nephrol 1998;9:1008–1017.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.