Abstract
Background/Aims: Experimental and clinical evidence has consistently demonstrated that renal macrophage infiltration is one of the most important events for the progression of diabetic nephropathy. Breviscapine is a flavonoid extracted from the Chinese herb Erigeron breviscapus. Previously, it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study is to investigate whether the renoprotective effect of breviscapine is through suppression of renal macrophage recruitment in diabetic rats. Methods: Diabetes was induced bystreptozotocin injection, and breviscapine was administered orally at a dose of 20 mg/kg/day for 8 weeks. Control rats received vehicle or breviscapine with the same schedule. Results: Breviscapine treatment markedly inhibited both an increase of albuminuria and glomeruli hypertrophy and tubulointerstitial injury without modifying mean arterial blood pressure and creatinine clearance. Levels of malondialdehyde and protein kinase C activities were markedly higher and antioxidant enzyme activities such as superoxide dismutase, catalase as well as glutathione peroxidase were significantly lower in the kidneys of diabetic rats than of the control group, breviscapine administration markedly remitted these changes. ED-1-positive cells and expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) in glomeruli and tubulointerstitium were all markedly elevated but were significantly reduced by breviscapine. Western blot analysis noted that the expression of transforming growth factor β1 protein was increased 1.8-fold in the kidney in diabetic rats, breviscapine treatment could reduce increased expression of TGF-β1 protein by 47%. Conclusion: This study describes a novel mechanism by which breviscapine confers a renoprotective effect.
Journal Section:
Original Paper
References
1.
Mensah-Brown EP, Obineche EN, Galadari S, Chandranath E, Shahin A, Ahmed I, Patel SM, Adem A: Streptozotocin-induced diabetic nephropathy in rats: the role of inflammatory cytokines. Cytokine 2005;31:180–190.
[PubMed]
2.
Galkina E, Ley K: Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol 2006;17:368–377.
[PubMed]
3.
Chow FY, Nikolic-Paterson DJ, Atkins RC, Tesch GH: Macrophages in streptozocin-induced diabetic nephropathy: potential role in renal fibrosis. Nephrol Dial Transplant 2004;19:2987–2996.
[PubMed]
4.
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]
5.
Sassy-Prigent C, Heudes D, Mandet C, Belair MF, Michel O, Perdereau B, Bariety J, Bruneval P: Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes 2000;49:466–475.
[PubMed]
6.
Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch G: Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int 2004;65:116–128.
[PubMed]
7.
Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, Ishibashi S: Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int 2004;66:1493–1502.
[PubMed]
8.
Romero F, Rodriguez-Iturbe B, Parra G, Gonzalez L, Herrera-Acosta J, Tapia E: Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999;55:945–955.
[PubMed]
9.
Utimura R, Fujihara CK, Mattar AL, Malheiros DM, Noronha IL, Zatz R: Mycophenolate mofetil prevents the development of glomerular injury in experiment diabetes. Kidney Int 2003;63:209–216.
[PubMed]
10.
Kikuchi Y, Imakiire T, Yamada M, Saigusa T, Hyodo T, Hyodo N, Suzuki S, Miura S: Mizoribine reduces renal injury and macrophage infiltration in non-insulin-dependent diabetic rats. Nephrol Dial Transplant 2005;20:1573–1581.
[PubMed]
11.
Zhang RW, Zhang YL, Wang JS, Lin YY, Shang B: Isolation and identification of flavoroids from shortscape fleabane (Erigeron breviscapus) (in Chinese). Chin Trad Herb Drugs 1988;19:199–201.
12.
Chen XX, He B, Chen YY: Mechanisms of inhibitory effects of breviscapine on lipid peroxidation in rat brain mitochondria (in Chinese). J Chin Pharm Sci 1998;7:209–213.
13.
Ali A, Gan L, Liu Q, Liu H, Xu HB: Antioxidant effect of scutellarin and its antagonistic action on the liver toxicity of Se in rats (in Chinese). Chin Pharmacol Bull 2003;19:113–115.
14.
Shuai J, Dong WW: Experimental research of PKC inhibitor, erigeron breviscapus on the ischemic/reperfusion brain injury (in Chinese). Chin Pharmacol Bull 1998;14:75–77.
15.
Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB: Role of high glucose-induced nuclear factor-κB activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol 2002;13:894–902.
[PubMed]
16.
Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, Strihou CY, Monnier VM, Witztum JL, Kurokawa K: Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 1997;100:2995–3004.
[PubMed]
17.
Trachtman H, Futterweit S, Maesaka J, Ma C, Valderrama E, Fuchs A, Tarectecan AA, Rao PS, Sturman JA, Boles TH: Taurine ameliorates chronic streptozocin-induced diabetic nephropathy in rats. Am J Physiol 1995;269:F429–F438.
18.
Ha H, Yu M-R, Kim KH: Melatonin and taurine reduce early glomerulopathy in diabetic rats. Free Radical Bio Med 1999;26:944–950.
[PubMed]
19.
Kim SS, Gallaher DD, Csallany AS: Vitamin E and probucol reduce urinary lipophilic aldehydes and renal enlargement in streptozotocin-induced diabetic rats. Lipids 2000;35:1225–1237.
[PubMed]
20.
Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GL, Kikkawa R: Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000;14:439–447.
[PubMed]
21.
Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA: Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med 2002;28:1456–1462.
22.
Park CW, Kim JH, Lee JH, Kim YS, Ahn HJ, Shin YS, Kim SY, Choi EJ, Chang YS, Bang BK: High glucose-induced intercellular adhesion molecule-1(ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-κB-dependent. Diabetologia 2000;43:1544–1553.
[PubMed]
23.
Kelly DJ, Chanty A, Gow RM, Zhang Y, Gilbert RE: Protein kinase C beta inhibition attenuates osteopontin expression, macrophage recruitment, and tubulointerstitial injury in advanced experimental diabetic nephropathy. J Am Soc Nephrol 2005;16:1654–1660.
[PubMed]
24.
Wu YG, Lin H, Qian H, Zhao M, Zhou D, Liang WN, Xu M, Zhang BK: Experimental study of effect of breviscapine on expression of transforming growth factor β1and connective tissue growth factor in kidney in diabetic rats (in Chinese). Chin Pharmacol Bull 2004;20:1050–1054.
25.
He W, Liu YM, Chen H, Zeng FD: Effect of breviscapine on brain edema and neutrophil infiltration induced by focal cerebral ischemia and reperfusion in rats (in Chinese). Chin J Pharmacol Toxicol 2004;18:161–165.
26.
Weibel ER: Stereological Methods: Practical Methods for Biological Morphometry. London, Academic Press, 1979, pp 162–203.
27.
Cao Z, Cooper ME, Wu LL, Cox AJ, Jandeleit-Dahm K, Kelly DJ, Gilbert RE: Blockade of the renin angiotensin and endothelin systems on progressive renal injury. Hypertension 2000;36:561–568.
[PubMed]
28.
Bradford MM: A rapid and sensitive method of the quantification of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 1976;72:248–254.
[PubMed]
29.
Kikkawa R, Haneda M, Uzu T, Koya D, Sugimoto T, Shigeta Y: Translocation of protein kinase C alpha and zeta in rat glomerular mesangial cells cultured under high glucose conditions. Diabetologia 1994;37:838–841.
[PubMed]
30.
Heasley LE, Johnson GL: Regulation of protein kinase C by nerve growth factor, epidermal growth factor, and phorbol esters in PC12 pheochromocytoma cells. J Biol Chem 1989;264:8646–8652.
[PubMed]
31.
Mai M, Geiger H, Hilgers KF, Veelken R, Mann JF, Dammrich J, Luft FC: Early interstitial changes in hypertension-induced renal injury. Hypertension 1993;22:754–765.
[PubMed]
32.
Bonnet F, Cooper ME, Kawachi H, Allen TJ, Boner G, Cao Z: Irbesartan normalizes the deficiency in glomerular nephrin expression in a model of diabetes and hypertension. Diabetologia 2001;44:874–877.
[PubMed]
33.
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]
34.
Aoyama I, Shimokata K, Niwa T: An oral adsorbent downregulates renal expression of genes that promote interstitial inflammation and fibrosis in diabetic rats. Nephron 2002;92:635–651.
[PubMed]
35.
Rothlein R, Wegner C: Role of intercellular adhesion molecule-1 in the inflammatory response. Kidney Int 1992;41:617–627.
[PubMed]
36.
Sugimoto H, Shikata K, Hirata K, Akiyama K, Matsuda M, Kushiro M, Shikata Y, Miyatake N, Miyasaka M, Makino H: Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation. Diabetes 1997;46:2075–2081.
[PubMed]
37.
Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y, Nagase R, Wada J, Shikata Y, Makino H: Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes 2003;52:2586–2593.
[PubMed]
38.
Banba N, Nakamura T, Matsumura M, Kuroda H, Hattori Y, Kasai K: Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy. Kidney Int 2000;58:684–690.
[PubMed]
39.
Ueda A, Okuda K, Ohno S, Shirai A, Igarashi T, Matsunaga K, Fukushima J, Kawamoto S, Ishigatsubo Y, Okubo T: NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. J Immunol 1994;153:2052–2063.
[PubMed]
40.
Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 1998;47:859–866.
[PubMed]
41.
Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000;49:1939–1945.
[PubMed]
42.
Studer RK, Craven PA, DeRubertix FR: Antioxidant inhibition of protein kinase C-signaled increase in transforming growth factor-beta in mesangial cells. Metabolism 1997;46:918–925.
[PubMed]
43.
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787–790.
[PubMed]
44.
Chen S, Jim B, Ziyadeh FN: Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol 2003;23:532–543.
[PubMed]
45.
Chneider A, Panzer U, Zahner G, Wenzel U, Wolf G, Thaiss F, Helmchen U, Stahl, RA: Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-β. Kidney Int 1999;56:135–144.
[PubMed]
© 2006 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.
2006
You do not currently have access to this content.
