Abstract
Background: Fractalkine is induced on activated endothelial cells and promotes strong adhesion of T cells and monocytes via its receptor CX3CR1. In kidney, fractalkine expression might be induced by high shear stress and play an important role in prolonged glomerular diseases. We examined whether fractalkine and CX3CR1 upregulation are found in streptozotocin-induced diabetic kidneys. Methods: Diabetic rats were randomized to receive an angiotensin-converting enzyme inhibitor (temocapril), aminoguanidine or no treatment. Reverse transcription-competitive polymerase chain reaction, Western blot analysis and immunohistochemistry were used. Results: At 4 weeks, fractalkine and CX3CR1 mRNA expression in diabetic kidneys increased compared with that in controls. Fractalkine staining in diabetic kidneys was clearly detected, along with glomerular capillary lumen and peritubular capillaries. A few CX3CR1 positive cell infiltration in diabetic glomeruli were found. Treatment with temocapril or aminoguanidine did not affect these changes. At 8 weeks, fractalkine and CX3CR1 mRNA expression in untreated diabetic kidneys markedly increased compared with that in controls. Membrane-anchored fractalkine protein expression in untreated diabetic rats also increased. The increased expression was suppressed by the treatment with temocapril and aminoguanidine. Increased CX3CR1-positive cell infiltration in diabetic glomeruli was also inhibited by both treatments. Some CX3CR1-positive cells were ED3 positive. Conclusions: Fractalkine and CX3CR1 upregulation were demonstrated in an early stage of diabetic kidney. These upregulation, as well as urinary albumin excretion, were suppressed by treatments with temocapril and aminoguanidine for 8 weeks. These findings suggest that fractalkine expression and CX3CR1-positive cell infiltration in diabetic kidneys might play an important role for progression of diabetic nephropathy.
Journal Section:
Original Paper
References
1.
Cooper ME: Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 2001;44:1957–1972.
[PubMed]
2.
Shikata K, Makino H: Role of macrophages in the pathogenesis of diabetic nephropathy. Contrib Nephrol. Basel, Karger, 2001, vol 134, pp 46–54.
3.
Furuta T, Saito T, Ootaka T, Soma J, Obara K, Abe K, Yoshinaga K: The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis 1993;21:480–485.
[PubMed]
4.
Sugimoto H, Shikata K, Hirata K, Akiyama K, Matsuda M, Kushiro M, Shikata Y, Miyataka N, Miyasaka M, Makino H: Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: Glomerular hypertension is a potential mechanism of ICAM-1 upregulation. Diabetes 1997;46:2075–2081.
[PubMed]
5.
Hirata K, Shikata K, Matsuda M, Akiyama K, Sugimoto H, Kushiro M, Makino H: Increased expression of selectins in kidneys of patients with diabetic nephropathy. Diabetologia 1998;41:185–192.
6.
Kato S, Luyckx VA, Ots M, Lee KW, Ziai F, Troy JL, Brenner BM, Mackenzie HS: Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney Int 1999;56:1037–1048.
[PubMed]
7.
Tashiro K, Koyanagi I, Saitoh A, Shimizu A, Shike T, Ishiguro C, Koizumi M, Funabiki K, Horikoshi S, Shirato I, Tomino Y: Urinary levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and renal injuries in patients with type 2 diabetic nephropathy. J Clin Lab Anal 2002;16:1–4.
8.
Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ: A new class of membrane-bound chemokine with a CX3C motif. Nature 1997;385:640–644.
[PubMed]
9.
Wong BW, Wong D, McManus BM: Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol 2002;11:332–338.
10.
Lesnik P, Haskell CA, Charo IF: Decreased atherosclerosis in CX3CR1 –/– mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003;111:333–340.
11.
Segerer S, Hughes E, Hudkins KL, Mack M, Goodpaster T, Alpers CE: Expression of the fractalkine receptor (CX3CR1) in human kidney diseases. Kidney Int 2002;62:488–495.
[PubMed]
12.
Feng L, Chen S, Garcia GE, Xia Y, Siani MA, Botti P, Wilson CB, Harrison JK, Bacon KB: Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1 rapid communication. Kidney Int 1999;56:612–620.
[PubMed]
13.
Ito Y, Kawachi H, Morioka Y, Nakatsue T, Koike H, Ikezumi Y, Oyanagi A, Natori Y, Natori Y, Nakamura T, Gejyo F, Shimizu F: Fractalkine expression and the recruitment of CX3CR1+ cells in the prolonged mesangial proliferative glomerulonephritis. Kidney Int 2002;61:2044–2057.
14.
Lewis EJ, Hunsicker LG, Gain RP, Rohde RD: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–1462.
[PubMed]
15.
Bucala R, Vlassara H: Advanced glycosylation end products in diabetic renal and vascular disease. Am J Kidney Dis 1995;26:875–888.
[PubMed]
16.
Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A: Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest 1997;99:278–287.
[PubMed]
17.
Kikuchi Y, Nonoguchi H, Machida K, Wakamatsu S, Koga H, Tomita K: Regulation of the apoptosis-related genes, Bax and Bcl-2, in the early stage of diabetes mellitus. Nephrology 2002;7:294–302.
18.
Soulis T, Cooper ME, Sastra S, Thallas V, Panagiotopoulos S, Bjerrum OJ, Jerums G: Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats. Diabetologia 1997;40:1141–1151.
19.
Forbes JM, Cooper ME, Thallas V, Burns WC, Thomas MC, Brammar GC, Lee F, Grant SL, Burrell LA, Jerums G, Osicka TM: Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes 2002;51:3274–3282.
[PubMed]
20.
Nakayama Y, Nonoguchi H, Kiyama S, et al: Intranephron distribution and regulation of endothelin-converting enzyme-1 in cyclosporin A-induced acute renal failure in rats. J Am Soc Nephrol 1999;10:562–571.
[PubMed]
21.
Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM: Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986;77:1925–1930.
[PubMed]
22.
Numabe A, Komatsu K, Frohlich ED: Effects of ANG-converting enzyme and alpha 1-adrenoceptor inhibition on intrarenal hemodynamics in SHR. Am J Physiol 1994;266:R1437–R1442.
23.
Kelly DJ, Gilbert RE, Cox AJ, Soulis T, Jerums G, Cooper ME: Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol 2001;12:2098–2107.
[PubMed]
24.
Twigg SM, Cao Z, MCLennan SV, Burns WC, Brammar G, Forbes JM, Cooper ME: Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine. Endocrinology 2002;143:4907–4915.
25.
Gogasyavuz D, Kucukkaya B, Ersoz HO, Yalcin AS, Emerk K, Akalin S: Effects of aminoguanidine on lipid and protein oxidation in diabetic rat kidneys. Int J Exp Diab Res 2002;3:145–151.
26.
Gilbert RE, Cox A, Wu LL, Allen TJ, Hulthen UL, Jerums G, Cooper ME: Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: Effects of ACE inhibition. Diabetes 1998;47:414–422.
[PubMed]
27.
de Cavanagh EM, Inserra F, Toblli J, Stella I, Fraga CG, Ferder L: Enalapril attenuates oxidative stress in diabetic rats. Hypertension 2001;38:1130–1136.
[PubMed]
28.
Miyata T, van Ypersele de Strihou C, Ueda Y, Ichimori K, Inagi R, Onogi H, Ishikawa N, Nangaku M, Kurokawa K: Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: Biochemical mechanisms. J Am Soc Nephrol 2002;13:2478–2487.
[PubMed]
29.
Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K, Wada J, Makino H: Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. Diabetologia 1998;41:1426–1434.
[PubMed]
© 2004 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.
