Abstract
Background/Aim: Extracellular matrix alterations are involved in the pathogenesis of diabetic nephropathy. We evaluated the effects of high glucose concentrations and inhibition of angiotensin-converting enzyme on the laminin and fibronectin production by glomerular epithelial cells. Methods: Glomerular epithelial cells were cultured in 5 and 30 mmol/l glucose, with and without enalaprilat (0.3 mmol/l). Laminin and fibronectin were measured (35S-methionine, immunoprecipitation), and their mRNA expression was evaluated (RT-PCR). Results: The laminin concentration was higher in the cells than in the medium, where an increase of its content was observed under high-glucose conditions (p < 0.01). Fibronectin, found only in the medium, was not modified by the high glucose concentration. Following enalaprilat administration, the laminin concentration was decreased under high-glucose conditions, both in the cell and in the medium (p < 0.001), whereas the fibronectin concentration was increased under high-glucose conditions (p < 0.001). The mRNA expression of laminin and fibronectin under high-glucose conditions only slightly increased. Enalaprilat decreased the fibronectin mRNA synthesis dramatically (>50%, p < 0.0001) under high-glucose conditions. Conclusions: Enalaprilat normalizes the abnormal, high-glucose-induced concentration of laminin, while it decreases the fibronectin synthesis. The improvement of the renal function in diabetic patients treated with angiotensin-converting enzyme inhibitors may, in part, be due to a modulator effect on extracellular matrix content and composition.
Journal Section:
Original Paper
References
1.
Striker GE, Peten EP, Carome MA, Pesce CM, Schmidt K, Yang CW, Elliot SJ, Striker LJ: The kidney disease of diabetes mellitus (KDDM): A cell and molecular biology approach. Diabetes Metab Rev 1993;9:37–56.
[PubMed]
2.
Kim TS, Kim JY, Hong HK, Lee HS: mRNA expression of glomerular basement membrane proteins and TGF-beta1 in human membranous nephropathy. J Pathol 1999;189:425–430.
3.
Sing AK, Mo WA, Dunea G, Arruda JA. Effect of glycated proteins on the matrix of glomerular epithelial cells. J Am Soc Nephrol 1998;9:802–810.
[PubMed]
4.
McLennan SV, Kelly DJ, Cox AJ, Cao Z, Lyons JG, Yue DK, Gilbert RE: Decreased matrix degradation in diabetic nephropathy: Effects of ACE inhibition on the expression and activities of matrix metalloproteinases. Diabetologia 2002;45:268–275.
5.
Olgemöller B, Schleicher E: Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy. Clin Investig 1993;71(5 suppl):13–19.
6.
Ruiz-Ortega M, González S, Serón D, Condom E, Buston C, Largo R: ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in a normotensive rat model of immune complex nephritis. Kidney Int 1995;48:1778–1791.
[PubMed]
7.
Weber H, Taylor DS, Molloy CJ: Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. J Clin Invest 1994;93:788–797.
[PubMed]
8.
Hahn A, Kern F, Bühler FR, Resink TJ: The renin-angiotensin system and extracellular matrix. Clin Investig 1993;71(5 suppl):7–12.
9.
Lai KN, Leung JC, Lai KB, To WY, Yeung VT, Lai FM: Gene expression of the renin-angiotensin system in human kidney. J Hypertens 1998;16:91–102.
[PubMed]
10.
Molitich ME: ACE inhibitors and diabetic nephropathy. Diabetes Care 1994;17:756–760.
11.
Sharma M, Sharma R, Greene AS, McCarthy ET, Savin VJ: Documentation of angiotensin II receptors in glomerular epithelial cells. Am J Physiol 1998;274:F623–F627.
12.
Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH: Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 2000;57:601–606.
[PubMed]
13.
Hernandez Mijares A, Barbera Comes G, Lluch Verdu I, Morillas Arino C, Real Collado J, Lorente Calvo R, Gonzalez Bayo E, Carmena Rodriguez R: Effect of enalapril on microalbuminuria and lipid profile of normotensive type I diabetes mellitus patients. Rev Clin Esp 1996;196:354–358.
14.
Kedziora-Kornatowska K: Effect of angiotensin convertase inhibitors and AT1 angiotensin receptor antagonists on the development of oxidative stress in the kidney of diabetic rats. Clin Chim Acta 1999;287:19–27.
15.
Kuriyama S, Tomonari H, Abe A, Imasawa T, Hosoya T: Beneficial effect of combination therapy with an angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor on overt proteinuria in a patient with type 1 diabetic nephropathy. Nephron 2000;86 529–530.
16.
Remuzzi A, Ruggenenti P, Mosconi L, Pata V, Viberti GC, Remuzzi G: Effect of low-dose enalapril on glomerular size selectivity in human diabetic nephropathy. J Nephrol 1993;6:36–43.
17.
Lapinski R, Perico N, Remuzzi A, Sangalli F, Benigni A, Remuzzi G: Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney. J Am Soc Nephrol 1996;7:653–660.
[PubMed]
18.
Striker GE, Killen PD, Farin FM: Human glomerular cells in vitro: Isolation and characterization. Transplant Proc 1980;12(Suppl 1):88–99.
19.
MacKay K, Striker LJ, Stauffer JW, Doi T, Agodoa LY, Striker GE: Transforming growth factor-beta: Murine glomerular receptors and responses of isolated glomerular cells. J Clin Invest 1989;83:1160–1167.
[PubMed]
20.
Conti FG, Striker LJ, Elliot SJ, Andreani D, Striker GE: Synthesis and release of insulinlike growth factor I by mesangial cells in culture. Am J Physiol 1988;255:F1214–F1219.
21.
Guh JY, Yang ML, Yang YL, Chang CC, Chuang LY: Captopril reverses high glucose-induced growth effects on LLC-PK cells partly by decreasing transforming growth factor-beta receptor protein expressions. J Am Soc Nephrol 1996;7:1207–1215.
[PubMed]
22.
Andreoli SP: Captopril scavenges hydrogen peroxide and reduces, but does not eliminate, oxidant-induced cell injury. Am J Physiol 1993;264:F120–F127.
23.
Scarpa S, D’Orazi G, Modesti A, Valia S, Zucco F, Stammati AL: Expression and synthesis of fibronectin and laminin by an intestinal epithelial cell line. Tissue Cell 1988;20:305–312.
24.
Agliano AM, Naso G, Silvestri I, Gradilone A, Vercillo R, Napolitano M, Gazzaniga P, Gandini O, Realacci M, Santangelo C, Saccani G, Manzari V, Frati L: Involvement of bcl-2 and bax gene expression in apoptosis and differentiation of the non-tumorigenic murine hematopoietic cell line, 32DC13(G). Int J Oncol 1997;11:1271–1277.
25.
Morano S, Guidobaldi L, Cipriani R, Gabriele A, Pantellini F, Medici F, D’ Erme M, Di Mario U: High glucose modifies heparan sulphate synthesis by mouse glomerular epithelial cells. Diabetes Metab Res Rev 1999;15:13–20.
[PubMed]
26.
Oh JH, Ha H, Yu MR, Lee HB: Sequential effects of high glucose on mesangial cell transforming growth factor-beta 1 and fibronectin synthesis. Kidney Int 1998;54:1872–1878.
[PubMed]
27.
Noble NA, Border WA: Angiotensin II in renal fibrosis: Should TGF-beta rather than blood pressure be the therapeutic target? Semin Nephrol 1997;17:455–466.
[PubMed]
© 2003 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.
2004
You do not currently have access to this content.
