Abstract
All-trans-retinoic acid (ATRA), a vitamin A derivative, was reported to suppress the interleukin-6 (IL-6) production and to downregulate the IL-6 receptor (IL-6R) and/or its signal transducer glycoprotein 130. We investigated the in vivo antinephritic effect of ATRA on IL-6 transgenic mice which had developed mesangial proliferative glomerulonephritis (PGN) as well as its in vitro inhibitory effect on the proliferation of rat mesangial cells. In vivo experiments on IL-6 transgenic mice showed that ATRA administration suppressed proteinuria and hematuria and reduced the IL-6 concentrations; furthermore, histological examination demonstrated that it improved PGN. In vitro experiments using rat mesangial cells demonstrated that ATRA inhibited cell growth in a dose-dependent manner within a range from 10–4 to 10–6M. This inhibition by ATRA was partially counteracted by the addition of IL-6. RT-PCR assay results showed that ATRA also reduced IL-6R, but not the glycoprotein 130 expression in mesangial cells. These findings indicate that, by blocking of the IL-6 function, ATRA may be therapeutically effective in PGN.
Journal Section:
Original Paper
References
1.
Chida Y, Tomura S, Takeuchi J: Renal survival rate of IgA nephropathy. Nephron 1985;40:189–194.
[PubMed]
2.
D’Amico G, Imbasciati E, Barbiano Di Belgioioso GB, Bertoli S, Fogazzi G, Ferrario F, Fellin G, Ragni A, Colasanti G, Minetti L, Ponticelli C: Idiopathic IgA mesangial nephropathy: Clinical and histological study of 374 patients. Medicine (Baltimore) 1985;64:49–60.
[PubMed]
3.
Leaker B, Fairley KF, Dowling J, Kincaid-Smith P: Lupus nephritis: Clinical and pathological correlation. Q J Med 1987;62:163–179.
4.
Gladman DD, Urowitz MB, Cole E, Ritchie S, Chang CH, Churg J: Kidney biopsy in SLE. I. A clinical-morphologic evaluation. Q J Med 1989;73:1125–1133.
5.
Donadio JV Jr, Hart GM, Bergstralh EJ, Holley KE: Prognostic determinants in lupus nephritis: A long-term clinicopathologic study. Lupus 1995;4:109–115.
[PubMed]
6.
Wagner J, Dechow C, Morath C, Lehrke I, Amann K, Waldherr R, Floege J, Ritz E: Retinoic acid reduces glomerular injury in a rat model of glomerular damage. J Am Soc Nephrol 2000;11:1479–1487.
[PubMed]
7.
Morath C, Dechow C, Lehrke I, Haxsen V, Waldherr R, Floege J, Ritz E, Wagner J: Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis. J Am Soc Nephrol 2001;12:2300–2309.
[PubMed]
8.
Dechow C, Morath C, Peters J, Lehrke I, Waldherr R, Haxsen V, Ritz E, Wagner J: Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis. Am J Physiol Renal Physiol 2001;281:F909–F919.
9.
Ogata A, Nishimoto N, Shima Y, Yoshizaki K, Kishimoto T: Inhibitory effect of all-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction. Blood 1994;84:3040–3046.
[PubMed]
10.
Akira S, Taga T, Kishimoto T: Interleukin-6 in biology and medicine. Adv Immunol 1993;54:1–78.
[PubMed]
11.
Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H, Fujii Y, Dohi K, Ishikawa H, Ohmoto Y, Yoshizaki K, Hirano T, Kishimoto T: Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol 1989;143:3949–3955.
[PubMed]
12.
Eitner F, Westerhuis R, Burg M, Weinhold B, Gröne HJ, Ostendorf T, Rüther U, Koch KM, Rees AJ, Floege J: Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo. Kidney Int 1997;51:69–78.
[PubMed]
13.
Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano N, Ohno S, Miyazaki S, Yamamura K, Hirano T, Kishimoto T: IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 1989;86:7547–7551.
[PubMed]
14.
Dohi K, Iwano M, Muraguchi A, Horii Y, Hirayama T, Ogawa S, Shiiki S, Hirano T, Kishimoto T, Ishikawa H: The prognostic significance of urinary interleukin 6 in IgA nephropathy. Clin Nephrol 1991;35:1–5.
[PubMed]
15.
Iwano M, Dohi K, Hirata E, Kurumatani N, Horii Y, Shiiki H, Fukatsu A, Matsuda T, Hirano T, Kishimoto T, Ishikawa H: Urinary levels of IL-6 in patients with active lupus nephritis. Clin Nephrol 1993;40:16–21.
[PubMed]
16.
Katsume A, Saito H, Yamada Y, Yorozu K, Ueda O, Akamatsu K, Nishimoto N, Kishimoto T, Yoshizaki K, Ohsugi Y: Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman’s disease like symptoms emerged in IL-6 transgenic mice. Cytokine 2002;20:304–311.
[PubMed]
17.
Bronstein I, Edwards B, Voyta JC: 1,2-Dioxetanes: Novel chemiluminescent enzyme substrates. Applications to immunoassays. J Biolumin Chemilumin 1989;4:99–111.
[PubMed]
18.
Foidart JB, Dechenne CA, Mahieu P, Creutz CE, de Mey J: Tissue culture of normal rat glomeruli: Isolation and morphological characterization of two homogeneous cell lines. Invest Cell Pathol 1979;2:15–26.
[PubMed]
19.
Hazen-Martin DJ, Chao CC, Wang IY, Sens DA, Garvin AJ, Wang AC: Developmental pattern of Thy-1 immunoreactivity in the human kidney and the application to pediatric renal neoplasms. Pediatr Pathol 1993;13:37–52.
[PubMed]
20.
Argiles A, Mourad G, Basset N, Axelrud-Cavadore C, Haiech J, Mion C, Cavadore JC, Demaille JG: Acute adaptive changes to unilateral nephrectomy in humans. Kidney Int 1987;32:714–720.
[PubMed]
21.
Jacques EA, Buschmann RJ, Layden TJ: The histopathologic progression of vitamin A-induced hepatic injury. Gastroenterology 1979;76:599–602.
[PubMed]
22.
Miyazaki J, Appella E, Ozato K: Negative regulation of the major histocompatibility class I gene in undifferentiated embryonal carcinoma cells. Proc Natl Acad Sci USA 1986;83:9537–9541.
[PubMed]
23.
Takitani K, Tamai H, Morinobu T, Kawamura N, Miyake M, Fujimoto T, Mino M: Pharmacokinetics of all-trans retinoic acid in pediatric patients with leukemia. Jpn J Cancer Res 1995;86:400–405.
[PubMed]
24.
Haberstroh U, Zahner G, Disser M, Thaiss F, Wolf G, Stahl RA: TGF-beta stimulates rat mesangial cell proliferation in culture: Role of PDGF beta-receptor expression. Am J Physiol 1993;264(2 Pt 2):F199–F205.
25.
Patel P, Varghese E, Ding G, Fan S, Kapasi A, Reddy K, Franki N, Nahar N, Singhal P: Transforming growth factor beta induces mesangial cell apoptosis through NO- and p53-dependent and -independent pathways. J Investig Med 2000;48:403–410.
[PubMed]
26.
Brinckerhoff CE, Sheldon LA, Benoit MC, Burgess DR, Wilder RL: Effect of retinoids on rheumatoid arthritis, a proliferative and invasive non-malignant disease. Ciba Found Symp 1985;113:191–211.
[PubMed]
27.
Kakizaki Y, Kraft N, Atkins RC: Differential control of mesangial cell proliferation by interferon-gamma. Clin Exp Immunol 1991;85:157–163.
[PubMed]
28.
Tan MS, Tsai JC, Lee YJ, Chen HC, Shin SJ, Lai YH, Perrella MA, Bianchi C, Higashiyama S, Endege W, Lee ME, Tsai JH: Induction of heparin-binding epidermal growth factor-like growth factor mRNA by protein kinase C activators. Kidney Int 1994;46:690–695.
[PubMed]
29.
Abboud HE, Poptic E, DiCorleto P: Production of platelet-derived growth factor like protein by rat mesangial cells in culture. J Clin Invest 1987;80:675–683.
[PubMed]
30.
Raynaud F, Gerbaud P, Gu XF, Donnadieu M, Evain-Brion D: Effect of retinoic acid on platelet-derived growth factor (PDGF) bioactivity and type-B PDGF receptors in normal and psoriatic human fibroblasts. J Invest Dermatol 1991;96:111–115.
[PubMed]
31.
Krust A, Kastner P, Petkovich M, Zelent A, Chambon P: A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci USA 1989;86:5310–5314.
[PubMed]
32.
Zelent A, Krust A, Petkovich M, Kastner P, Chambon P: Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature 1989;339:714–717.
[PubMed]
© 2005 S. Karger AG, Basel
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.
2005
You do not currently have access to this content.
