Background: This study was performed to investigate whether ginseng extract has a protective effect in an experimental mouse model of chronic cyclosporine (CsA) nephropathy. Methods: Mice were treated with CsA (30 mg/kg/day, subcutaneously) with or without Korean red ginseng extract (KRG) (0.2, 0.4 g/kg/day, orally) on a 0.01% salt diet for 4 weeks. The effect of KRG on CsA-induced renal injury was evaluated by assessing renal function and pathology, mediators of inflammation, tubulointerstitial fibrosis and apoptotic cell death. Using an in vitro model, we also examined the effect of KRG on CsA-treated proximal tubular cells (HK-2). Oxidative stress was measured by assessing 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in 24-hour urine, tissue sections, and culture media. Results: Four weeks of CsA treatment caused renal dysfunction, typical pathologic lesions and apoptotic cell death. KRG treatment reduced serum creatinine and blood urea nitrogen and histopathology and increased creatinine clearance. Proinflammatory and profibrotic molecules such as induced nitric oxide synthase, cytokines, transforming growth factor (TGF)-β1 and TGF-β1-inducible gene h3 and apoptotic cell death, also decreased with KRG treatment. Consistent with these results, in vitro studies showed that addition of KRG protected against CsA-induced morphological changes, cytotoxicity, inflammation, and apoptotic cell death as demonstrated by annexin V binding. These changes were accompanied by decrease in the level of 8-OHdG in urine and culture supernatant after KRG treatment. Conclusion: The results of our in vivo and in vitro studies demonstrate that KRG has a protective effect in CsA-induced renal injury via reducing oxidative stress.

Keywords:
Cyclosporine A, Nephropathy, Korean red ginseng, Oxidative stress, Apoptosis, Inflammation
1.
Yoon HE, Yang CW: Established and newly proposed mechanisms of chronic cyclosporine nephropathy. Korean J Intern Med 2009;24:81-92.
2.
Capasso G, Di Gennaro CI, Della Ragione F, Manna C, Ciarcia R, Florio S, Perna A, Pollastro RM, Damiano S, Mazzoni O, Galletti P, Zappia V: In vivo effect of the natural antioxidant hydroxytyrosol on cyclosporine nephrotoxicity in rats. Nephrol Dial Transplant 2008;23:1186-1195.
3.
Satyanarayana PS, Chopra K: Oxidative stress-mediated renal dysfunction by cyclosporine A in rats: attenuation by trimetazidine. Ren Fail 2002;24:259-274.
4.
Tariq M, Morais C, Sobki S, Al Sulaiman M, Al Khader A: N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats. Nephrol Dial Transplant 1999;14:923-929.
5.
Jung NP, Jin SH: Studies on the physiological and biochemical effects of Korean ginseng. Korean J Ginseng Sci 1996;20:431-471.
6.
Kim JH, Hahm DH, Yang DC, Kim JH, Lee HJ, Shim I: Effect of crude saponin of Korean red ginseng on high-fat diet-induced obesity in the rat. J Pharmacol Sci 2005;97:124-131.
7.
Choi YD, Xin ZC, Choi HK: Effect of Korean red ginseng on the rabbit corpus cavernosal smooth muscle. Int J Impot Res 1998;10:37-43.
8.
Jeon BH, Kim CS, Kim HS, Park JB, Nam KY, Chang SJ: Effect of Korean red ginseng on blood pressure and nitric oxide production. Acta Pharmacol Sin 2000;21:1095-1100.
9.
Ryu JK, Lee T, Kim DJ, Park IS, Yoon SM, Lee HS, Song SU, Suh JK: Free radical-scavenging activity of Korean red ginseng for erectile dysfunction in non-insulin-dependent diabetes mellitus rats. Urology 2005;65:611-615.
10.
Voces J, Alvarez AI, Vila L, Ferrando A, Cabral de Oliveira C, Prieto JG: Effects of administration of the standardized Panax ginseng extract g115 on hepatic antioxidant function after exhaustive exercise. Comp Biochemistry Physiol C Pharmacol Toxicol Endocrinol 1999;123:175-184.
11.
Yoon M, Lee H, Jeong S, Kim JJ, Nicol CJ, Nam KW, Kim M, Cho BG, Oh GT: Peroxisome proliferator-activated receptor alpha is involved in the regulation of lipid metabolism by ginseng. Br J Pharmacol 2003;138:1295-1302.
12.
Lim SW, Hyoung BJ, Piao SG, Doh KC, Chung BH, Yang CW: Chronic cyclosporine nephropathy is characterized by excessive autophagosome formation and decreased autophagic clearance. Transplantation 2012;94:218-225.
13.
Yang CW, Faulkner GR, Wahba IM, Christianson TA, Bagby GC, Jin DC, Abboud HE, Andoh TF, Bennett WM: Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice. Am J Transplant 2002;2:391-399.
14.
Ghee JY, Han DH, Song HK, Kim WY, Kim SH, Yoon HE, Choi BS, Kim YS, Kim J, Yang CW: The role of macrophage in the pathogenesis of chronic cyclosporine-induced nephropathy. Nephrol Dial Transplant 2008;23:4061-4069.
15.
Hong CE, Lyu SY: Anti-inflammatory and anti-oxidative effects of Korean red ginseng extract in human keratinocytes. Immune Netw 2011;11:42-49.
16.
Kang KS, Kim HY, Yamabe N, Nagai R, Yokozawa T: Protective effect of sun ginseng against diabetic renal damage. Biol Pharm Bull 2006;29:1678-1684.
17.
de Mattos AM, Olyaei AJ, Bennett WM: Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 2000;35:333-346.
18.
Sun BK, Li C, Lim SW, Jung JY, Lee SH, Kim IS, Kim YS, Kim J, Bang BK, Yang CW: Expression of transforming growth factor-beta-inducible gene-h3 in normal and cyclosporine-treated rat kidney. J Lab Clin Med 2004;143:175-183.
19.
Islam M, Burke JF, McGowan TA, Zhu Y, Dunn SR, McCue P, Kanalas J, Sharma K: Effect of anti-transforming growth factor-beta antibodies in cyclosporine-induced renal dysfunction. Kidney Int 2001;59:498-506.
20.
Oltvai ZN, Milliman CL, Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609-619.
21.
Kim EH LM, Kim IH, Pyo S, Choi KT, Rhee DK: Anti-apoptotic effects of red ginseng on oxidative stress induced by hydrogen peroxide in SK-N-SH cells. J Ginseng Res 2010;34:134-144.
22.
Lee Y KK, Bae HM, Lee YC, Choi SY: Protective effects of ginseng coffee against hydrogen peroxide-induced oxidative damage in L6 muscle cells. J Ginseng Res 2010;34:145-149.
23.
Park MS, Cho EJ, Lee SK, Lee EJ, Lee SD, Lee KH, Jeon BH: Korean red ginseng protects oxidative injury caused by lead poisoning. J Ginseng Res 2010;34:132-137.
24.
Im GJ, Chang JW, Choi J, Chae SW, Ko EJ, Jung HH: Protective effect of Korean red ginseng extract on cisplatin ototoxicity in HEI-OC1 auditory cells. Phytother Res 2010;24:614-621.
25.
Sung H, Jung Y-S, Cho Y-K: Beneficial effects of a combination of Korean red ginseng and highly active antiretroviral therapy in human immunodeficiency virus type 1-infected patients. Clin Vaccine Immunol 2009;16:1127-1131.
26.
Vuksan V, Sung M-K, Sievenpiper J, Stavro PM, Jenkins A, Di Buono M, Lee K-S, Leiter L, Nam K, Arnason J, Choi M, Naeem A: Korean red ginseng (Panax ginseng) improves glucose and insulin regulation in well-controlled, type 2 diabetes: results of a randomized, double-blind, placebo-controlled study of efficacy and safety. Nutr Metab Cardiovasc Dis 2008;18:46-56.
27.
He N, Edeki T: The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Am J Ther 2004;11:206-212.
28.
Gurley B, Gardner S, Hubbard M, Williams DK, Gentry WB, Cui Y, Ang CYW: Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002;72:276-287.
29.
Gurley B, Gardner S, Hubbard M, Williams DK, Gentry WB, Cui Y, Ang CYW: Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 2005;22:525-539.
© 2013 S. Karger AG, Basel
2013
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.