Abstract
Background: Renal tubule cell apoptosis plays a pivotal role in cisplatin-induced nephrotoxicity. α-Lipoic acid (LA), a thiol antioxidant, is well known to be cytoprotective in various cell death models through its involvement in the death receptor apoptosis pathway. However, we hypothesized that LA would attenuate cisplatin-induced nephrotoxicity through inhibition of mitochondrial bax translocation in rats. Methods and Materials: Sprague-Dawley rats were treated with cisplatin (7 mg/kg) with or without pretreatment with LA (100 mg/kg × 3 times). Renal function was evaluated based on blood urea nitrogen (BUN), serum creatinine, and fractional excretion of sodium. Tubular necrosis scores were assessed by light microscopy findings and apoptotic cell deaths by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Cytosolic bax, mitochondrial bax, cytochrome c, caspase-9 and caspase-3 were investigated using Western blot in each group. Results: LA pretreatment significantly decreased both BUN and serum creatinine. Morphologically, both tubular necrosis and apoptosis of tubular cells were decreased significantly with LA pretreatment. LA attenuated the translocation of mitochondrial bax, reduced the release of cytochrome c, and decreased the expression of caspase-3 and caspase-9 serially in cisplatin nephrotoxicity. Conclusion: We demonstrated that LA attenuates cisplatin-induced renal tubular damages by inhibition of mitochondrial bax translocation in vivo.
Journal Section:
Original Paper
Keywords:
Bax protein,
Apoptosis,
Mitochondria,
Thioctic acid,
Antioxidant,
Cisplatin,
Renal insufficiency
References
1.
Ries F, Klastersky J: Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 1986;13:368–379.
2.
Jiang M, Wei Q, Pabla N, Dong G, Wang CY, Yang T, Smith SB, Dong Z: Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. Biochem Pharmacol 2007;73:1499–1510.
[PubMed]
3.
Ramesh G, Reeves WB: Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-α. Kidney Int 2004;65:490–498.
[PubMed]
4.
Portilla D, Li S, Nagothu KK, Megyesi J, Kaissling B, Schnackenberg L, Safirstein RL, Beger RD: Metabolomic study of cisplatin induced nephrotoxicity. Kidney Int 2006;69:2194–2204.
[PubMed]
5.
Shutt TE, Shadel GS: Expanding the mitochondrial interactome. Genome Biol 2007;8:203.
[PubMed]
6.
Pabla N, Huang S, Mi QS, Daniel R, Dong Z: ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin- induced apoptosis. J Biol Chem 2008;283:6572–6583.
[PubMed]
7.
Tsuruya K, Tokumoto M, Ninomiya T, Hirakawa M, Masutani K, Taniguchi M, Fukuda K, Kanai H, Hirakata H, Iida M: Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways. Am J Physiol Renal Physiol 2003;285:208–218
8.
Lee RH, Song JM, Park MY, Kang SK, Kim YK, Jung JS: Cisplatin induced apoptosis by translocation of endogenous Bax in mouse collecting duct cell. Biochem Pharmacol 2001;62:1013–1023
[PubMed]
9.
Tsuruya K, Ninomiya T, Tokumoto M: Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 2003;63:72–82.
[PubMed]
10.
Liu H, Baliga R: Endoplasmic-reticulum stress-associated caspase 12 mediates cisplatin-induced LLC-PK1 cell apoptosis. J Am Soc Nephrol 2005;16:1985–1992.
[PubMed]
11.
Jiang M, Wei Q, Wang J, Du Q, Yu J, Zhang L, Dong Z: Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis. Oncogene 2006;25:4056–4066.
[PubMed]
12.
Wei Q, Dong G, Franklin J, Dong Z: The pathologic role of Bax in cisplatin nephrotoxicity. Kidney Int 2007;72:53–62.
[PubMed]
13.
Packer L, Witt EH, Tritschler HJ: Alpha-lipoic acid as a biological anti-oxidant. Free Radic Biol Med 1995;19:227–250.
[PubMed]
14.
Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM: Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem 2004;11:1135–1146.
[PubMed]
15.
Kim HS, Kim HJ, Park KG, Kim YN, Kwon TK, Park JY, Lee KU, Kim JG, Lee IK: Alpha-lipoic acid inhibits matrix metalloproteinase-9 expression by inhibiting NF-kappaB transcriptional activity. Exp Mol Med 2007;39:106–113.
[PubMed]
16.
Gupta S, Knowlton AA: HSP60, Bax, apoptosis and the heart. J Cell Mol Med 2005:9;51–58.
[PubMed]
17.
Kim BJ, Ryu SW, Song BJ: JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 2006;281:21256–21265.
[PubMed]
18.
Park MS, De Leon M, Devarajan P: Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol 2002;13:858–865.
[PubMed]
19.
Nagothu KK, Bhatt R, Kaushal GP, Portilla D: Fibrate prevents cisplatin-induced proximal tubule cell death. Kidney Int 2005;68:2680–2693.
[PubMed]
20.
Gross A, Pilcher K, Blachly-Dyson E, Basso E, Jockel J, Bassik MC, Korsmeyer SJ, Forte M: Biochemical and genetic analysis of the mitochondrial response of yeast to Bax and Bcl-XL. Mol Cell Biol 2000;20:3125–3136
[PubMed]
21.
Mignotte B, Vayssiere JL: Mitochondria and apoptosis. Eur J Biochem 1998;252:1–15.
[PubMed]
22.
Banki K, Hutter E, Gonchoroff NJ, Perl A: Elevation of mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling. J Immunol 1999;162:1466–1479
[PubMed]
23.
Kaushal GP, Kaushal V, Hong X, Shah SV: Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells. Kidney Int 2001;60:1726–1736.
[PubMed]
24.
Zhang WJ, Frei B: Alpha-lipoic acid inhibits TNF-alpha-induced NF-kB activation and adhesion molecule expression in human aortic endothelial cells. FASEB 2001;15:2423–2432.
[PubMed]
25.
Lee KM, Park KG, Kim YD, Lee HJ, Kim HT, Cho WH, Kim HS, Han SW, Koh GY, Park JY, Lee KU, Kim JG, Lee IK: Alpha-lipoic acid inhibits fractalkine expression and prevents neointimal hyperplasia after balloon injury in rat carotid artery. Atherosclerosis 2006;189:106–114.
[PubMed]
26.
Byun CH, Koh JM, Kim DK, Park SI, Lee KU, Kim GS: Alpha-lipoic acid inhibits TNF-α-induced apoptosis in human bone marrow stromal cells. J Bone Miner Res 2007;20:1125–1135.
27.
Zhang WJ, Wei H, Hagen T, Frei B: α-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci USA 2007;104:4077–4082.
[PubMed]
28.
Itoh N, Nagata S: A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen J Biol Chem 1993;268:10932–10937.
29.
Tartaglia LA, Ayres TM, Wong GH, Goeddel DV: A novel domain within the 55kd TNF receptor signals cell death. Cell 1993;74:845–853.
[PubMed]
30.
Nguyen M, Millar DG, Yong VW, Korsmeyer SJ, Shore GC: Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 1993;268:25265–25268.
[PubMed]
31.
Wang J, Biju MP, Wang MH, Haase VH, Dong Z: Cytoprotective effects of hypoxia against cisplatin-induced tubular cell apoptosis: involvement of mitochondrial inhibition and p53 suppression. J Am Soc Nephrol 2006;17:1875–1885.
[PubMed]
32.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G: Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441–446.
[PubMed]
33.
Lin J, Bierhaus A, Bugert P: Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy. Diabetologia 2006;49:1089–1096.
[PubMed]
34.
Melhem MF, Craven PA, Liachenko J, Derubertis FR: α-Lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes. J Am Soc Nephrol 2002;13:108–116.
[PubMed]
35.
Takaoka M, Ohkita M, Kobayashi Y, Yuba M, Matsumura Y: Protective effect of α-lipoic acid against ischaemic acute renal failure in rats. Clin Exp Pharmacol Physiol 2002;29:189–194.
[PubMed]
36.
Ziegler D: Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical review. Treat Endocrinol 2004;3:173–189.
[PubMed]
37.
Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, Khan BV: Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the irbesartan and lipoic acid in endothelial dysfunction (ISLAND) study. Circulation 2005;111:343–348.
[PubMed]
38.
Kahler W, Kuklinski B, Ruhlmann C, Plotz C: Diabetes mellitus-A free radical associated disease: effects of adjuvant supplementation of antioxidants. Frankfurt am Main, pmi Verl-Gruppe, 1993, pp 33–53.
39.
Eun Hui Bae, Kyun Sang Lee, Jong Un Lee, Seong Kwon Ma, Nam Ho Kim, Ki Chul Choi, Jørgen Frøkiær, Søren Nielsen, Sun Young Kim, Sung Zoo Kim, Suhn Hee Kim, and Soo Wan Kim: Effects of α-lipoic acid on ischemia-reperfusion-induced renal dysfunction in rats. Am J Physiol Renal Physiol 2008;294:272–280.
40.
Diesel B, Kulhanek-Heinze S, Holtje M: Lipoic acid as a directly binding activator of the insulin receptor: protection from hepatocyte apoptosis. Biochemistry 2007;46:2146–2155.
[PubMed]
© 2009 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.
2009
You do not currently have access to this content.
