DOI QR코드

DOI QR Code

Autophagy localization and cytoprotective role in cisplatin-induced acute kidney injury

  • Karunasagara, Shanika (Department of Veterinary Medicine & Institute of Veterinary Science, College of Veterinary Medicine, Chungnam National University) ;
  • Hong, Geum-Lan (Department of Veterinary Medicine & Institute of Veterinary Science, College of Veterinary Medicine, Chungnam National University) ;
  • Jung, Da-Young (Department of Veterinary Medicine & Institute of Veterinary Science, College of Veterinary Medicine, Chungnam National University) ;
  • Ryu, Si-Yun (Department of Veterinary Medicine & Institute of Veterinary Science, College of Veterinary Medicine, Chungnam National University) ;
  • Jung, Ju-Young (Department of Veterinary Medicine & Institute of Veterinary Science, College of Veterinary Medicine, Chungnam National University)
  • Received : 2019.05.16
  • Accepted : 2019.06.28
  • Published : 2019.09.30

Abstract

Autophagy is a fundamental cellular process that maintains homeostasis and cell integrity, under stress conditions. Although the involvement of autophagy in various conditions has been elucidated, the role of autophagy in renal structure is not completely clarified. Our aim was to investigate the cytoprotective effect of autophagy against acute kidney injury (AKI) through cisplatin deteriorative pathway, which leads to AKI via renal cell degradation. For in vivo experiments, male Sprague Dawley rats were divided in to 2 groups (n = 6/group) as control, Cis-5D. Following a single intraperitoneal injection of cisplatin, rats were sacrificed after 5 days. Blood urea nitrogen (BUN), creatinine (Cr) and histological alterations were examined. Further, expression of key regulators of autophagy, light-clain 3 (LC3), p62, and Beclin1, was evaluated by immunohistochemistry (IHC). The rats exhibited severe renal dysfunction, indicated by elevated BUN, Cr. Hematoxylin and eosin staining revealed histological damages in cisplatin-treated rats. Furthermore, IHC analysis revealed increased expression of LC3, Beclin1 and decreased expression of p62. Furthermore, expression of aforementioned autophagy markers was restricted to proximal tubule. Taken together, our study demonstrated that cisplatin can cause nephrotoxicity and lead to AKI. This phenomenon accelerated autophagy in renal proximal tubules and guards against AKI.

Keywords

References

  1. Oh GS, Kim HJ, Shen A, Lee SB, Khadka D, Pandit A, So HS. Cisplatin-induced kidney dysfunction and perspectives on improving treatment strategies. Electrolyte Blood Press 2014;12:55-65. https://doi.org/10.5049/EBP.2014.12.2.55
  2. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci 2007;334:115-124. https://doi.org/10.1097/MAJ.0b013e31812dfe1e
  3. Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 2003;14:2199-2210. https://doi.org/10.1097/01.ASN.0000079785.13922.F6
  4. Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 2006;17:1503-1520. https://doi.org/10.1681/ASN.2006010017
  5. Goligorsky MS. Whispers and shouts in the pathogenesis of acute renal ischaemia. Nephrol Dial Transplant 2005;20:261-266. https://doi.org/10.1093/ndt/gfh182
  6. Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 2004;66:496-499. https://doi.org/10.1111/j.1523-1755.2004.761_5.x
  7. Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 2008;48:463-493. https://doi.org/10.1146/annurev.pharmtox.48.113006.094615
  8. Sastry J, Kellie SJ. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. Pediatr Hematol Oncol 2005;22:441-445. https://doi.org/10.1080/08880010590964381
  9. Pfeifer U, Guder WG. Stimulation of cellular autophagy by parathyroid hormone and cyclic adenosine 3',5': monophosphate in isolated tubular fragments from the rat's kidney cortex. Virchows Arch B Cell Pathol Incl Mol Pathol 1975;19:51-67.
  10. Pfeifer U, Scheller H. A morphometric study of cellular autophagy including diurnal variations in kidney tubules of normal rats. J Cell Biol 1975;64:608-621. https://doi.org/10.1083/jcb.64.3.608
  11. Livingston MJ, Dong Z. Autophagy in acute kidney injury. Semin Nephrol 2014;34:17-26. https://doi.org/10.1016/j.semnephrol.2013.11.004
  12. Bolisetty S, Traylor AM, Kim J, Joseph R, Ricart K, Landar A, Agarwal A. Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury. J Am Soc Nephrol 2010;21:1702-1712. https://doi.org/10.1681/ASN.2010030238
  13. Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int 2012;82:1271-1283. https://doi.org/10.1038/ki.2012.261
  14. Periyasamy-Thandavan S, Jiang M, Wei Q, Smith R, Yin XM, Dong Z. Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int 2008;74:631-640. https://doi.org/10.1038/ki.2008.214
  15. Brady HR, Kone BC, Stromski ME, Zeidel ML, Giebisch G, Gullans SR. Mitochondrial injury: an early event in cisplatin toxicity to renal proximal tubules. Am J Physiol 1990;258:F1181-F1187. https://doi.org/10.1152/ajpheart.1990.258.4.H1181
  16. Gordon JA, Gattone VH 2nd. Mitochondrial alterations in cisplatin-induced acute renal failure. Am J Physiol 1986;250:F991-F998. https://doi.org/10.1152/ajpregu.1986.250.6.R991
  17. Miller RP, Tadagavadi RK, Ramesh G, Reeves WB. Mechanisms of Cisplatin nephrotoxicity. Toxins (Basel) 2010;2:2490-2518. https://doi.org/10.3390/toxins2112490
  18. Pezeshki Z, Khosravi A, Nekuei M, Khoshnood S, Zandi E, Eslamian M, Talebi A, Emami SN, Nematbakhsh M. Time course of cisplatin-induced nephrotoxicity and hepatotoxicity. J Nephropathol 2017;6:163-167. https://doi.org/10.15171/jnp.2017.28
  19. Liu Q, Hu S, He Y, Zhang J, Zeng X, Gong F, Liang L. The protective effects of Zhen-Wu-Tang against cisplatininduced acute kidney injury in rats. PLoS One 2017;12:e0179137. https://doi.org/10.1371/journal.pone.0179137
  20. Kuhlmann MK, Burkhardt G, Kohler H. Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application. Nephrol Dial Transplant 1997;12:2478-2480. https://doi.org/10.1093/ndt/12.12.2478
  21. Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct 2002;27:421-429. https://doi.org/10.1247/csf.27.421
  22. Tanaka Y, Kume S, Kitada M, Kanasaki K, Uzu T, Maegawa H, Koya D. Autophagy as a therapeutic target in diabetic nephropathy. Exp Diabetes Res 2012;2012:628978.
  23. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, Amano A, Yoshimori T. Autophagosomes form at ER-mitochondria contact sites. Nature 2013;495:389-393. https://doi.org/10.1038/nature11910
  24. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 2009;10:458-467. https://doi.org/10.1038/nrm2708
  25. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010;90:1383-1435. https://doi.org/10.1152/physrev.00030.2009
  26. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 2005;171:603-614. https://doi.org/10.1083/jcb.200507002
  27. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 2007;131:1149-1163. https://doi.org/10.1016/j.cell.2007.10.035
  28. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature 1999;402:672-676. https://doi.org/10.1038/45257
  29. Rubinstein AD, Kimchi A. Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci 2012;125:5259-5268. https://doi.org/10.1242/jcs.115865
  30. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B. Protection against fatal Sindbis virus encephalitis by Beclin, a novel Bcl-2-interacting protein. J Virol 1998;72:8586-8596. https://doi.org/10.1128/JVI.72.11.8586-8596.1998
  31. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011;18:571-580. https://doi.org/10.1038/cdd.2010.191