Retinoic acid (RA) is recently used for the treatment of experimental glomerular diseases. However, mechanisms underlying its therapeutic effects are largely unknown. We recently reported that RA has the potential for protecting certain cells from particular injury. A typical example is its effect on oxidant-induced apoptosis of mesangial cells. Mesangial cells exposed to hydrogen peroxide undergo apoptosis through activation of the c-Jun N-terminal kinase activator protein 1 pathway. RA dramatically inhibits this process via suppression of c-fos/c-jun expression and inhibition of the c-Jun N-terminal kinase activation. The anti-apoptotic effect of RA is mediated by both nuclear receptor dependent and nuclear receptor independent mechanisms and is, at least in part, mediated by induction of mitogen-activated protein kinase phosphatase 1. In this review, we briefly summarize the current knowledge on molecular mechanisms involved in the anti-apoptotic effects of RA.

Keywords:
Retinoic acid, Mesangial cell, Oxidative stress, Apoptosis, Mitogen-activated protein kinase phosphatase 1 (MKP-1)
1.
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.
2.
Moreno-Manzano V, Muñoz JCS, Jimenez FJR, Mampaso F, Puyol DR, Puyol MR, Lucio-Cazana FJ: All-trans-retinoic acid treatment inhibits mononuclear infiltration in puromycin aminonucleoside nephritis (abstract). J Am Soc Nephrol 2000;11:511A.
3.
Moreno-Manzano V, Rodriguez-Puyol M, Arribas-Gomez I, Rodriguez-Puyol D, Lucio-Cazana FJ: Prevention by tretinoin (all-trans-retinoic acid) of age-related renal changes. Int J Vitam Nutr Res 1997;67:427–431.
4.
Wagner J: Potential role of retinoids in the therapy of renal disease. Nephrol Dial Transplant 2001;16:441–444.
5.
Thacher SM, Vasudevan J, Chandraratna RA: Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 2000;6:25–58.
6.
Morath C, Dechow C, Lehrke I, Ihling C, Floege J, Ritz E: Retinoic acid suppresses TGF-β overexpression in a rat model of glomerular damage (abstract). J Am Soc Nephrol 1999;10:532A.
7.
Dechow C, Haxsen V, Waldherr R, Ritz E, Wagner J: Retinoids influence the expression of the renin-angiotensin system in nephritic glomeruli (abstract). J Am Soc Nephrol 2000;11:505A.
8.
Manzano VM, Muñoz JC, Jimenez JR, Puyol MR, Puyol DR, Kitamura M, Lucio-Cazana FJ: Human renal mesangial cells are a target for the anti-inflammatory action of 9-cis retinoic acid. Br J Pharmacol 2000;131:1673–1683.
9.
Datta PK, Lianos EA: Retinoic acids inhibit inducible nitric oxide synthase expression in mesangial cells. Kidney Int 1999;56:486–493.
10.
Lucio-Cazana J, Nakayama K, Xu Q, Konta T, Moreno-Manzano V, Furusu A, Kitamura M: Suppression of constitutive but not IL-1β-inducible expression of monocyte chemoattractant protein-1 in mesangial cells by retinoic acids: Intervention in the activator protein-1 pathway. J Am Soc Nephrol 2001;12:688–694.
11.
Han JY, Han SY, Yoon JW, Jo SK, Kim NH, Cha WY, Kim HK, Cha DR: Retinoic acid inhibits high glucose and cytokine stimulated production of vascular endothelial growth factor (VEGF) in mesangial cells (abstract). J Am Soc Nephrol 2000;11:488A.
12.
Savill J: Regulation of glomerular cell number by apoptosis. Kidney Int 1999;56:1216–1222.
13.
Moreno-Manzano V, Ishikawa Y, Lucio-Cazana J, Kitamura M: Suppression of apoptosis by all-trans-retinoic acid: Dual intervention in the c-Jun N-terminal kinase-AP-1 pathway. J Biol Chem 1999;274:20251–20258.
14.
De Luca LM: Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J 1991;5:2924–2933.
15.
Schule R, Rangarajan P, Yang N, Kliewer S, Ransone LJ, Bolado J, Verma IM, Evans RM: Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci USA 1991;88:6092–6096.
16.
Ahlemeyer B, Bauerbach E, Plath M, Steuber M, Heers C, Tegtmeier F, Krieglstein J: Retinoic acid reduces apoptosis and oxidative stress by preservation of SOD protein level. Free Radic Biol Med 2001;30:1067–1077.
17.
Ahlemeyer B, Huhne R, Krieglstein J: Retinoic acid potentiated the protective effect of NGF against staurosporine-induced apoptosis in cultured chick neurons by increasing the trkA protein expression. J Neurosci Res 2000;60:767–778.
18.
Simonson MS: Anti-AP-1 activity of all-trans retinoic acid in glomerular mesangial cells. Am J Physiol 1994;267:F805–F815.
19.
Ishikawa Y, Yokoo T, Kitamura M: c-Jun/ AP-1, but not NF-κB, is a mediator for oxidant-initiated apoptosis in glomerular mesangial cells. Biochem Biophys Res Commun 1997;240:496–501.
20.
Chambon P: A decade of molecular biology of retinoic acid receptors. FASEB J 1996;10:940–954.
21.
Konta T, Xu Q, Furusu A, Nakayama K, Kitamura M: Selective roles of retinoic acid receptor and retinoid X receptor in the suppression of apoptosis by all-trans-retinoic acid. J Biol Chem 2001;276:12697–12701.
22.
Keyse SM, Emslie EA: Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 1992;359:644–647.
23.
Lee HY, Sueoka N, Hong WK, Mangelsdorf DJ, Claret FX, Kurie JM: All-trans-retinoic acid inhibits Jun N-terminal kinase by increasing dual-specificity phosphatase activity. Mol Cell Biol 1999;19:1973–1980.
24.
Reffas S, Schlegel W: Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells. Biochem J 2000;352:701–708.
25.
Xu Q, Konta T, Furusu A, Nakayama K, Lucio-Cazana J, Fine LG, Kitamura M: Involvement of mitogen-activated protein kinase phosphatase 1 in mediating the anti-apoptotic effect of retinoic acids (abstract). J Am Soc Nephrol 2001;12:604A.
26.
Moreno-Manzano V, Ishikawa Y, Lucio-Cazana J, Kitamura M: Selective involvement of superoxide anion, but not downstream compounds hydrogen peroxide and peroxynitrite, in tumor necrosis factor-α-induced apoptosis of rat mesangial cells. J Biol Chem 2000;275:12684–12691.
27.
Mattana J, Ahmed S, Gibbons N, Reddy K: Retinoic acid receptor stimulation induces apoptosis of human mesangial cells (abstract). J Am Soc Nephrol 2000;11:461A.
28.
Manzano VM, Puyol MR, Puyol DR, Cazana FJ: Tretinoin prevents age-related renal changes and stimulates antioxidant defenses in cultured renal mesangial cells. J Pharmacol Exp Ther 1999;289:123–132.
29.
Ahlemeyer B, Bauerbach E, Plath M, Steuber M, Heers C, Tegtmeier F, Krieglstein J: Retinoic acid reduces apoptosis and oxidative stress by preservation of SOD protein level. Free Radic Biol Med 2001;30:1067–1077.
30.
Chadwick CC, Shaw LJ, Winneker RC: TNF-α and 9-cis-retinoic acid synergistically induce ICAM-1 expression: Evidence for interaction of retinoid receptors with NF-κB. Exp Cell Res 1998;239:423–429.
© 2002 S. Karger AG, Basel
2002
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.