Background/Aims: Both activation of the polyol pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the interaction between these two pathways using normal mesangial cells (MCs) and transgenic (TG) MCs with elevated aldose reductase (AR) activity. Methods: TG mice with expression of the human AR (hAR) gene in kidney MCs were established. Mouse glomeruli and primary cultures of MCs from hAR TG and wild-type (WT) mice were studied regarding the changes in AR activity, transforming growth factor-β1 (TGF-β1) and type IV collagen mRNA and protein levels, in response to BSA modified by advanced glycation end-products (AGE-BSA). Results: Ex vivo addition of AGE-BSA increased AR activity, TGF-β1 and type IV collagen mRNA levels in both WT and TG glomeruli, with greater rise in TG glomeruli. These increments were attenuated by zopolrestat, an AR inhibitor. In cultured MCs, AGE-BSA enhanced AR activity, TGF-β1 and type IV collagen mRNA and protein levels both in WT and TG MCs, again with greater increases in TG MCs. The AGE-induced enhancement in TGF-β1 and type IV collagen expression were suppressed by either zopolrestat or transfection with an AR antisense oligonucleotide. Conclusion: These data suggest that the activation of the polyol pathway by AGEs, more marked in genetic conditions with increased AR activity, may contribute to the pathogenesis of diabetic glomerulopathy, through enhancing mesangial cell expression of TGF-β1 and type IV collagen.

Friedman EA: Diabetic nephropathy: Strategies in prevention and management. Kidney Int 1982;21:780–791.
Dunlop M: Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int 2000;58(suppl):3–12.
Oates PJ: Diabetic nephropathy, renal hemodynamics, and aldose reductase inhibitors. Drug Dev Res 1994;32:104–116.
Brownlee M: Lilly Lecture 1993. Glycation and diabetic complications. Diabetes 1994;43:836–841.
Kinoshita JH, Nishimura C: The involvement of aldose reductase in diabetes complications. Diabet Metab Rev 1988;4:323–337.
Liu YF, Wat NM, Chung SS, KO BC, Lam KS: Diabetic nephropathy is associated with the 5′-end dinucleotide repeat polymorphism of the aldose reductase gene in Chinese subjects with type 2 diabetes. Diabet Med 2002;19:113–118.
Shah VO, Scavini M, Nikolic J, Sun Y, Vai S, Griffith JK, Dorin RI, Stidley C, Yacoub M, Vander Jagt DL, Eaton RP, Zager PG: Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy. J Clin Endocrinol Metab 1998;83:2886–2891.
Hodgkinson AD, Sondergaard KL, Yang B, Cross DF, Millward BA, Demaine AG: Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy. Kidney Int 2001;60:211–218.
Ishii H, Tada H, Isogai S: An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-β and protein kinase C activity in cultured mesangial cells. Diabetologia 1998;41:362–364.
Iehara N, Takeoka H, Yamada Y, Kita T, Doi T: Advanced glycation end products modulate transcriptional regulation in mesangial cells. Kidney Int 1996;50:1166–1172.
Pugliese G, Pricci F, Romeo G, Pugliese F, Mene P, Giannini S, Gresci B, Galli G, Rotella CM, Vlassara H, Di Mario U: Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated mechanism. Diabetes 1997;46:1881–1887.
Yang CW, Vlassara H, Peten EP, He CJ, Striker GE, Striker LJ: Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci USA 1994;91:9436–9440.
Suarez G, Rajaram R, Bhuyan KC, Oronsky AL, Goidl JA: Administration of an aldose reductase inhibitor induces a decrease of collagen fluorescence in diabetic rats. J Clin Invest 1988;82:624–627.
Nakamura N, Yamazaki K, Satoh A, Urakaze M, Kobayashi M, Yamabe H, Osawa H, Shirato K, Sugawara T, Nakamura M, Tamaura M, Okumua K: Effects of epalrestat on plasma levels of advanced glycation end products in patients with type 2 diabetes. In Vivo 2003;17:177–180.
Nakamura N, Obayashi H, Fujii M, Fukui M, Yoshimori, Ogata M, Hasegawa G, Shigeta H, Kitagawa Y, Yoshikawa T, Kondo M, Ohta M, Nishimura M, Nishinaka T, Nishimura CY: Induction of aldose reductase in cultured human microvascular endothelial cells by advanced glycation end products. Free Radic Biol Med 2000;29:17–25.
Mylari BL, Larson ER, Beyer TA, Zembrowski WJ, Aldinger CE, Dee MF, Siegel TW, Singleton DH: Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid (zopolrestat) and congeners. J Med Chem 1991;34:108–122.
Lee AYW Chung SK, Chung SSM: Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc Natl Acad Sci USA 1995;92:2780–2784.
Chung S, Lamendola J: Cloning and sequence determination of human placental aldose reductase gene. J Biol Chem 1989;264:14775–14777.
Wu H, Moulton K, Horvai A, Parik S, Glass CK: Combinatorial interactions between AP-1 and ets domain proteins contribute to the developmental regulation of the macrophage scavenger receptor gene. Mol Cell Biol 1994;14:2129–2139.
Yamaoka T, Nishimura C, Yamashita K, Itakura M, Yamada T, Fujimoto J, Kokai Y: Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA. Diabetologia 1995;38:255–261.
Alric C, Pecher C, Cellier E, Schanstra JP, Poirier B, Chevalier J, Bascands JL, Girolami JP: Inhibition of IGF-I-induced Erk1 and 2 activation and mitogenesis in mesangial cells by bradykinin. Kidney Int 2002;62:412–421.
Mackay K, Striker LJ: Glomerular epithelial, mesangial, and endothelial cells lines from transgenic mice. Kidney Int 1988;33:677–684.
Nishinaka T, Yabe-Nishimura C: EGF receptor-ERK pathway is the major signaling pathway that mediates upregulation of aldose reductase expression under oxidative stress. Free Radic Biol Med 2001;31:205–216.
Ramana KV, Friedrich B, Bhatnagar A, Srivastava SK: Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-α in human lens epithelial cells. Faseb J 2003;17:315–317.
Takemura T, Yoshioka K, Aya N, Murakami K, Matumoto A, Itakura H, Kodama T, Suzuki H, Maki S: Apolipoproteins and lipoprotein receptors in glomeruli in human kidney diseases. Kidney Int 1993;43:918–927.
Ruan XZ, Varghse Z, Powis SH, Moorhead JF: Human mesangial cells express inducible macrophage scavenger receptor. Kidney Int 1999;56:440–451.
Song Z, Fu DT, Chan YS, Leung S, Chung SS, Chung SK: Transgenic mice overexpressing aldose reductase is Schwann cells show more severe nerve conduction velocity deficit and oxidative stress under hyperglycemic stress. Mol Cell Neurosci 2003;23:638–647.
Iwashima Y, Eto M, Hata A, Kaku K, Horiuchi S, Ushikubi F, Sano H: Advanced glycation end products-induced gene expression of scavenger receptors in cultured human monocyte-derived macrophages. Biochem Biophys Res Commun 2000;277:368–380.
Nakamura J, Kasuya J, Hamada Y, Nakashima E, Naruse K, Yasuda Y, Kato K, Hotta N: Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity. Diabetologia 2001;44:480–487.
Kapor-Drezgic J, Zhou X, Babazono T, Dlugosz JA, Hohman T, Whiteside C: Effect of high glucose on mesangial cell protein kinase C-δ and -ε is polyol pathway-dependent. J Am Soc Nephrol 1999;10:1193–1203.
Shaw S, Wang X, Redd H, Alexander GD, Isales CM, Marrero MB: High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway. J Biol Chem 2003;278:30634–30641.
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.