Background/Aim: Diabetes and mesangial stretch caused by hypertension increase mesangial matrix deposition which is induced by local production of transforming growth factor beta 1 (TGF-β1). Both conditions are associated with cortical GLUT1 overexpression. We evaluated the effect of genetically determined hypertension and its association with diabetes on urinary TGF-β1 and cortical GLUT1 and GLUT2 expression. Methods: We studied Wistar-Kyoto rats (controls, C) and spontaneously hypertensive rats (SHR), weighing ∼210 g, 30 days after the injection of streptozotocin (diabetic, D) or citrate buffer (10 C, 9 SHR, 12 C-D and 15 SHR-D). Twenty-four-hour urine was collected for glucose, albumin, and TGF-β1 determinations. Catheters were implanted into the femoral artery to measure the arterial blood pressure in conscious animals 1 day later. Then GLUT1 and GLUT2 protein levels (Western blotting) in renal cortex and medulla were evaluated. Results: The cortical GLUT1 levels were 5, 2, and 7 times higher in SHR, C-D, and SHR-D groups versus C group (p < 0.05); the GLUT2 contents were 1.5, 1.8, and 2.3 times higher in SHR, C-D and SHR-D groups versus C group (p < 0.05). The urinary TGF-β1 level was elevated by diabetes and diabetes and hypertension, but not by hypertension alone: 1.39 ± 0.2, 2.34 ± 0.6, 18.2 ± 3.2, and 28.8 ± 7.6 ng/24 h, respectively, in C, SHR, C-D, and SHR-D groups (p < 0.05). Conclusions: Diabetes, hypertension, and especially their association increase the renal cortical GLUT1 and GLUT2 levels. The magnitude of GLUT1 overexpression caused by hypertension is higher than that induced by diabetes alone. The impact on urinary TGF-β1 occurs when diabetes and hypertension are associated, suggesting an effect that is triggered in the presence of GLUT1 overexpression and hyperglycemia.

Keywords:
Diabetic nephropathy, Transforming growth factor beta 1, Albuminuria, Streptozotocin-induced diabetes, Glucose transporters
1.
Parving HH, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PA: Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J (Clin Res Ed) 1987;294:1443–1447.
2.
UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.
3.
UK Prospective Diabetes Study (UKPDS) Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 1998;317:703–713.
4.
Cooper ME: Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 2001;44:1957–1972.
5.
Bertoluci MC, Schmid H, Lachat JJ, Coimbra TM: Transforming growth factor-beta in the development of rat diabetic nephropathy: A 10-month study with insulin-treated rats. Nephron 1996;74:189–196.
6.
D’Agord Schaan B, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H: Increased renal GLUT1 abundance and urinary TGF-β1 in streptozotocin-induced diabetic rats: Implications for the development of nephropathy complicating diabetes. Horm Metab Res 2001;33:664–669.
7.
D’Agord Schaan B, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H: Impact of renal denervation on renal content of GLUT1, albuminuria, and urinary TGF-β1 in streptozotocin-induced diabetic rats. Auton Neurosci 2003;104:88–94.
8.
Dominguez JH, Camp K, Maianu L, Feister H, Garvey WT: Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats. Am J Physiol 1994;266(2 Pt 2):F283–F290.
9.
D’Agord Schaan B, Lacchini S, Schmid H, Irigoyen MC, Okamoto MM, Machado UF: Modulation of facilitative glucose transporters in diabetes and renal denervation (poster 1805). 18th Int Diabetes Federation Congr, Paris 2003.
10.
Zhang J, Liu Z, Liu D, Li L: Identification of glucose transporter-1 and its functional assay in mouse glomerular mesangial cells cultured in vitro. Chin Med Sci J 2001;16:35–39.
11.
Li Y, Liu Z, Liu D, Zhang J, Chen Z, Li L: Identification and function of glucose transporter 1 in human mesangial cells. Chin Med J (Engl) 2001;114:824–828.
12.
Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P: Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose millieu mimics the diabetic phenotype. J Clin Invest 1995;96:1802–1814.
13.
Zhu J, Liu Z, Li Y: Inhibition of glucose transporter 1 overexpression in mesangial cells by rhein (in Chinese). Zhonghua Nei Ke Za Zhi 2001;40:537–542.
14.
Cortes P, Zhao X, Riser BL, Narins RG: Role of glomerular mechanical strain in the pathogenesis of diabetic nephropathy. Kidney Int 1997;51:57–68.
15.
Hirakata M, Kaname S, Chung UG, Joki N, Hori Y, Noda M, Takuwa Y, Okazaki T, Fujita T, Katoh T, Kurokawa K: Tyrosine kinase dependent expression of TGF-beta induced by stretch in mesangial cells. Kidney Int 1997;51:1028–1036.
16.
Schaan BD, Maeda CY, Timm HB, Medeiros S, Moraes RS, Ferlin E, Fernandes TG, Ribeiro JP, Schmid H, Irigoyen MC: Time course of changes in heart rate and blood pressure variability in streptozotocin-induced diabetic rats treated with insulin. Braz J Med Biol Res 1997;30:1081–1086.
17.
Cooper ME, Allen TJ, Macmillan P, Bach L, Jerums G, Doyle AE: Genetic hypertension accelerates nephropathy in the streptozotocin diabetic rat. Am J Hypertens 1988;1:5–10.
18.
Righetti AE, Boer-Lima PA, Lopes de Faria JB: The presence of genetic hypertension stimulates early renal accumulation of fibronectin in experimental diabetes mellitus. Diabetologia 2001;44:2088–2091.
19.
Nose A, Mori Y, Uchiyama-Tanaka Y, Kishimoto N, Maruyama K, Matsubara H, Iwasaka T: Regulation of glucose transporter (GLUT1) gene expression by angiotensin II in mesangial cells: Involvement of HB-EGF and EGF receptor transactivation. Hypertens Res 2003;26:67–73.
20.
Gnudi L, Viberti G, Raij L, Rodriguez V, Burt D, Cortes P, Hartley B, Thomas S, Maestrini S, Gruden G: GLUT-1 overexpression: Link between hemodynamic and metabolic factors in glomerular injury? Hypertension 2003;42:19–24.
21.
Arendshorst WJ, Beierwaltes WH: Renal and nephron hemodynamics in spontaneously hypertensive rats. Am J Physiol 1979;236:F246–F251.
22.
Vestri S, Okamoto MM, de Freitas HS, Aparecida Dos Santos R, Nunes MT, Morimatsu M, Heimann JC, Machado UF: Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol 2001;182:105–112.
23.
Vestri S, Nikami M, Saito M, Machado UF: Production of antisera to synthetic decapeptide of the COOH-terminus of rat GLUT2. Braz Arch Biol Technol 1998;41:194–198.
24.
Tolbert EM, Weisstuch J, Feiner HD, Dworkin LD: Onset of glomerular hypertension with aging precedes injury in the spontaneously hypertensive rat. Am J Physiol Renal Physiol 2000;278:F839–F846.
25.
Zatz R, Meyer TW, Rennke HG, Brenner BM: Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci USA 1985;82:5963–5967.
26.
Obata J, Nakamura T, Takano H, Naito A, Kimura H, Yoshida Y, Shimizu F, Guo DF, Inagami T: Increased gene expression of components of the renin-angiotensin system in glomeruli of genetically hypertensive rats. J Hypertens 2000;18:1247–1255.
27.
Quinn LA, McCumbee WD: Regulation of glucose transport by angiotensin II and glucose in cultured vascular smooth muscle cells. J Cell Physiol 1998;177:94–102.
28.
Winternitz SR, Katholi RE, Oparil S: Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat. J Clin Invest 1980;66:971–978.
29.
Noonan WT, Shapiro VM, Banks RO: Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. Life Sci 2001;68:2967–2977.
30.
Marks J, Carvou NJ, Debnam ES, Srai SK, Unwin RJ: Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol 2003;553(Pt 1):137–145.
31.
Gaede P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study. Lancet 1999;353:617–622.
32.
Waeber G, Thompson N, Nicod P, Bonny C: Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. Mol Endocrinol 1996;10:1327–1334.
33.
Kim JW, Ahn YH: CCAAT/enhancer binding protein regulates the promoter activity of the rat GLUT2 glucose transporter gene in liver cells. Biochem J 1998;336(Pt 1):83–90.
34.
Kim HI, Kim JW, Kim SH, Cha JY, Kim KS, Ahn YH: Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter. Diabetes 2000;49:1517–1524.
35.
Cha JY, Kim H, Kim KS, Hur MW, Ahn Y: Identification of transacting factors responsible for the tissue-specific expression of human glucose transporter type 2 isoform gene: Cooperative role of hepatocyte nuclear factors 1 alpha and 3 beta. J Biol Chem 2000;275:18358–18365.
36.
Wang X, Zhou J, Doyle ME, Egan JM: Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic beta-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism. Endocrinology 2001;142:1820–1827.
37.
Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A: Regulation of glut1 mRNA by hypoxia-inducible factor-1: Interaction between H-ras and hypoxia. J Biol Chem 2001;276:9519–9525.
38.
Kainer DB, Doris PA: Cyclophilin B expression in renal proximal tubules of hypertensive rats. Hypertension 2000;35:958–964.
39.
Inoki K, Haneda M, Maeda S, Koya D, Kikkawa R: TGF-β1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int 1999;55:1704–1712.
40.
Heilig CW, Liu Y, England RL, Freytag SO, Gilbert JD, Heilig KO, Zhu M, Concepcion LA, Brosius FC 3rd: D-Glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: Implications for diabetic nephropathy. Diabetes 1997;46:1030–1039.
41.
Gruden G, Zonca S, Hayward A, Thomas S, Maestrini S, Gnudi L, Viberti G: Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes 2000;49:655–661.
42.
Singh R, Alavi N, Singh AK, Leehey DJ: Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation. Diabetes 1999;48:2066–2073.
43.
Leehey DJ, Singh AK, Alavi N, Singh R: Role of angiotensin II in diabetic nephropathy. Kidney Int Suppl 2000;77:S93–S98.
44.
Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH: Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively. Kidney Int 2001;60:277–283.
45.
Cooper ME, Allen TJ, O’Brien RC, Macmillan PA, Clarke B, Jerums G, Doyle AE: Effects of genetic hypertension on diabetic nephropathy in the rat – functional and structural characteristics. J Hypertens 1988;6:1009–1016.
46.
Asada T, Ogawa T, Iwai M, Shimomura K, Kobayashi M: Recombinant insulin-like growth factor I normalizes expression of renal glucose transporters in diabetic rats. Am J Physiol 1997;273(1 Pt 2):F27–F37.
© 2005 S. Karger AG, Basel
2005
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.