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http://dx.doi.org/10.1016/j.jgr.2016.12.013

Protective effect of ginsenoside Rb1 against tacrolimus-induced apoptosis in renal proximal tubular LLC-PK1 cells  

Lee, Dahae (School of Pharmacy, Sungkyunkwan University)
Lee, Dong-Soo (Institute of Human-Environment Interface Biology, Biomedical Research Institute, Department of Dermatology, Seoul National University College of Medicine)
Jung, Kiwon (College of Pharmacy, CHA University)
Hwang, Gwi Seo (College of Korean Medicine, Gachon University)
Lee, Hye Lim (College of Korean Medicine, Gachon University)
Yamabe, Noriko (College of Korean Medicine, Gachon University)
Lee, Hae-Jeong (Department of Food and Nutrition, Gachon University)
Eom, Dae-Woon (Department of Pathology, University of Ulsan College of Medicine)
Kim, Ki Hyun (School of Pharmacy, Sungkyunkwan University)
Kang, Ki Sung (College of Korean Medicine, Gachon University)
Publication Information
Journal of Ginseng Research / v.42, no.1, 2018 , pp. 75-80 More about this Journal
Abstract
Background: The aim of the present study was to evaluate the potential protective effects of six ginsenosides (Rb1, Rb2, Rc, Rd, Rg1, and Rg3) isolated from Panax ginseng against tacrolimus (FK506)-induced apoptosis in renal proximal tubular LLC-PK1 cells. Methods: LLC-PK1 cells were treated with FK506 and ginsenosides, and cell viability was measured. Protein expressions of mitogen-activated protein kinases, caspase-3, and kidney injury molecule-1 (KIM-1) were evaluated by Western blotting analyses. The number of apoptotic cells was measured using an image-based cytometric assay. Results: Reduction in cell viability by $60{\mu}M$ FK506 was ameliorated significantly by cotreatment with ginsenosides Rg1 and Rb1. The phosphorylation of p38, extracellular signal-regulated kinases, and KIM-1, and cleavage of caspase-3, increased markedly in LLC-PK1 cells treated with FK506 and significantly decreased after cotreatment with ginsenoside Rb1. The number of apoptotic cells decreased by 6.0% after cotreatment with ginsenoside Rb1 ($10{\mu}M$ and $50{\mu}M$). Conclusion: The antiapoptotic effects of ginsenoside Rb1 on FK506-induced apoptosis were mediated by the inhibition of mitogen-activated protein kinases and caspase activation.
Keywords
caspase-3; FK506-induced nephrotoxicity; ginsenoside Rb1; KIM-1; MAPKs;
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1 Lim SW, Doh KC, Jin L, Jin J, Piao SG, Heo SB, Chung BH, Yang CW. Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy. Nephrology 2014;19:490-9.   DOI
2 Park JY, Choi P, Kim T, Ko H, Kim HK, Kang KS, Ham J. Protective effects of processed finseng and its active ginsenosides on cisplatin-induced nephrotoxicity: in vitro and in vivo studies. J Agric Food Chem 2015;63:5964-9.   DOI
3 Fan Y, Xia J, Jia D, Zhang M, Zhang Y, Huang G, Wang Y. Mechanism of ginsenoside Rg1 renal protection in a mouse model of d-galactose-induced subacute damage. Pharm Biol 2016;54:1815-21.   DOI
4 Wang L, Mao N, Tan RZ, Wang HL, Wen J, Liu YH, Furhad M, Fan JM. Ginsenoside Rg1 reduces aldosterone-induced autophagy via the AMPK/mTOR pathway in NRK-52E cells. Int J M Med 2015;36:518-26.   DOI
5 Sun Q, Meng QT, Jiang Y, Liu HM, Lei SQ, Su WT, Duan WN, Wu Y, Xia ZY, Xia ZY. Protective effect of ginsenoside Rb1 against intestinal ischemia-reperfusion induced acute renal injury in mice. PloS One 2013;8:e80859.   DOI
6 Choi SJ, You HS, Chung SY. Tacrolimus-induced apoptotic signal transduction pathway. Transplant Proc 2008;40:2734-6.   DOI
7 Harris RC. COX-2 and the kidney. J Cardiovasc Pharmacol 2006;47:S37-42.   DOI
8 Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell deathdapoptosis, autophagy and senescence. FEBS J 2010;277:2-21.   DOI
9 Cassidy H, Radford R, Slyne J, O'Connell S, Slattery C, Ryan MP, McMorrow T. The role ofMAPKin drug-induced kidney injury. J Sig Transduct 2012;2012:463617.
10 Lu Z, Xu S. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB life 2006;58:621-31.   DOI
11 Deschesnes RG, Huot J, Valerie K, Landry J. Involvement of p38 in apoptosisassociated membrane blebbing and nuclear condensation. Mol Biol Cell 2001;12:1569-82.   DOI
12 Al-Harbi NO, Imam F, Al-Harbi MM, Iqbal M, Nadeem A, Al-Shahrah OA, Korashy HM, Al-Hosaini KA, Ahmed M, Bahashwar S. Treatment with aliskiren ameliorates tacrolimus-induced nephrotoxicity in rats. J Renin Angiotensin Aldosterone Syst 2015;16:1329-36.   DOI
13 Wallemacq PE, Reding R. FK506 (tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects. Clin Chem 1993;39:2219-28.
14 Cosner D, Zeng X, Zhang PL. Proximal tubular injury in medullary rays is an early sign of acute tacrolimus nephrotoxicity. J Transplant 2015;2015:142521.
15 Cai B, Chang SH, Becker EB, Bonni A, Xia Z. p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem 2006;281:25215-22.   DOI
16 Farley N, Pedraza-Alva G, Serrano-Gomez D, Nagaleekar V, Aronshtam A, Krahl T, Thornton T, Rincon M. p38 mitogen-activated protein kinase mediates the Fas-induced mitochondrial death pathway in CD8+ T cells. Mol Cell Biol 2006;26:2118-29.   DOI
17 Zou W, Zeng J, Zhuo M, Xu W, Sun L, Wang J, Liu X. Involvement of caspase-3 and p38 mitogen-activated protein kinase in cobalt chloride-induced apoptosis in PC12 cells. J Neurosci Res 2002;67:837-43.   DOI
18 Dumont FJ. FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 2000;7:731-48.   DOI
19 Tada H, Nakashima A, Awaya A, Fujisaki A, Inoue K, Kawamura K, Itoh K, Masuda H, Suzuki T. Effects of thymic hormone on reactive oxygen speciesscavengers and renal function in tacrolimus-induced nephrotoxicity. Life Sci 2002;70:1213-23.   DOI
20 Hisamura F, Kojima-Yuasa A, Huang X, Kennedy DO, Matsui-Yuasa I. Synergistic effect of green tea polyphenols on their protection against FK506- induced cytotoxicity in renal cells. Am J Chin Med 2008;36:615-24.   DOI
21 Hisamura F, Kojima-Yuasa A, Kennedy DO, Matsui-Yuasa I. Protective effect of green tea extract and tea polyphenols against FK506-induced cytotoxicity in renal cells. Basic Clin Pharmacol Toxicol 2006;98:192-6.   DOI
22 Zhong Z, Connor HD, Li X, Mason RP, Forman DT, Lemasters JJ, Thurman RG. Reduction of ciclosporin and tacrolimus nephrotoxicity by plant polyphenols. J Pharm Pharmacol 2006;58:1533-43.   DOI
23 Yang B, El Nahas AM, Thomas GL, Haylor JL, Watson PF, Wagner B, Johnson TS. Caspase-3 and apoptosis in experimental chronic renal scarring. Kidney Int 2001;60:1765-76.   DOI
24 Nielsen FT, Leyssac PP, Kemp E, Starklint H, Dieperink H. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995;10:334-40.
25 Servais H, Ortiz A, Devuyst O, Denamur S, Tulkens PM, Mingeot-Leclercq MP. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanismsand potential approaches tomodulation.Apoptosis 2008;13:11-32.   DOI
26 Havasi A, Borkan SC. Apoptosis and acute kidney injury. Kidney Int 2011;80: 29-40.   DOI
27 Humphreys BD, Xu F, Sabbisetti V, Grgic I, Movahedi Naini S, Wang N, Chen G, Xiao S, Patel D, Henderson JM, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 2013;123:4023-35.   DOI
28 Back JH, Ryu HH, Hong R, Han SA, Yoon YM, Kim DH, Hong SJ, Kim HL, Chung JH, Shin BC, et al. Antiproteinuric effects of green tea extract on tacrolimus-induced nephrotoxicity in mice. Transplant Proc 2015;47:2032-4.   DOI
29 Park JY, Choi P, Kim HK, Kang KS, Ham J. Increase in apoptotic effect of Panax ginseng by microwave processing in human prostate cancer cells: in vitro and in vivo studies. J Ginseng Res 2016;40:62-7.   DOI
30 Park EH, Kim YJ, Yamabe N, Park SH, Kim HK, Jang HJ, Kim JH, Cheon GJ, Ham J, Kang KS. Stereospecific anticancer effects of ginsenoside Rg3 epimers isolated from heat-processed American ginseng on human gastric cancer cell. J Ginseng Res 2014;38:22-7.   DOI
31 Jang HJ, Han IH, Kim YJ, Yamabe N, Lee D, Hwang GS, Oh M, Choi KC, Kim SN, Ham J, Eom DW, et al. Anticarcinogenic effects of products of heat-processed ginsenoside Re, a major constituent of ginseng berry, on human gastric cancer cells. J Agric Food Chem 2014;62:2830-6.   DOI
32 Kang KS, Kim HY, Yamabe N, Park JH, Yokozawa T. Preventive effect of 20(S)-ginsenoside Rg3 against lipopolysaccharide-induced hepatic and renal injury in rats. Free Radic Res 2007;41:1181-8.   DOI
33 Kang KS, Yamabe N, Kim HY, Park JH, Yokozawa T. Therapeutic potential of 20(S)-ginsenoside Rg(3) against streptozotocin-induced diabetic renal damage in rats. Eur J Pharmacol 2008;591:266-72.   DOI
34 Zhou T, Zu G, Zhang X, Wang X, Li S, Gong X, Liang Z, Zhao J. Neuroprotective effects of ginsenoside Rg1 through the Wnt/beta-catenin signaling pathway in both in vivo and in vitro models of Parkinson's disease. Neuropharmacology 2016;101:480-9.   DOI
35 Kang KS, Kim HY, Baek SH, Yoo HH, Park JH, Yokozawa T. Study on the hydroxyl radical scavenging activity changes of ginseng and ginsenoside-Rb2 by heat processing. Biol Pharm Bull 2007;30:724-8.   DOI
36 Lee YJ, Kim HY, Kang KS, Lee JG, Yokozawa T, Park JH. The chemical and hydroxyl radical scavenging activity changes of ginsenoside-Rb1 by heat processing. Bioorg Med Chem Lett 2008;18:4515-20.   DOI
37 Lee W, Park SH, Lee S, Chung BC, Song MO, Song KI, Ham J, Kim SN, Kang KS. Increase in antioxidant effect of ginsenoside Re-alanine mixture by Maillard reaction. Food Chem 2012;135:2430-5.   DOI
38 Cong L, Chen W. Neuroprotective effect of ginsenoside Rd in spinal cord injury rats. Basic Clin Pharmacol Toxicol 2016;119:193-201.   DOI
39 Dong X, Zheng L, Lu S, Yang Y. Neuroprotective effects of pretreatment of ginsenoside Rb1 on severe cerebral ischemia-induced injuries in aged mice: involvement of anti-oxidant signaling. Geriatr Gerontol Int 2015. http://dx.doi.org/10.1111/ggi.12699.   DOI
40 Li YB, Wang Y, Tang JP, Chen D, Wang SL. Neuroprotective effects of ginsenoside Rg1-induced neural stem cell transplantation on hypoxic-ischemic encephalopathy. Neural Regen Res 2015;10:753-9.   DOI
41 Shin HS, Yu M, Kim M, Choi HS, Kang DH. Renoprotective effect of red ginseng in gentamicin-induced acute kidney injury. Lab Invest 2014;94:1147-60.   DOI
42 Doh KC, Lim SW, Piao SG, Jin L, Heo SB, Zheng YF, Bae SK, Hwang GH, Min KI, Chung BH, et al. Ginseng treatment attenuates chronic cyclosporine nephropathy via reducing oxidative stress in an experimental mouse model. Am J Nephrol 2013;37:421-33.   DOI