Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

  • Ahn, Joon-Ik (Pharmacological Research Division, Toxicological Evaluation Research Department, National Institute of Food and Drug Safety Evaluation) ;
  • Baik, Si-Yeon (Pharmacological Research Division, Toxicological Evaluation Research Department, National Institute of Food and Drug Safety Evaluation) ;
  • Ko, Moon-Jeong (Pharmacological Research Division, Toxicological Evaluation Research Department, National Institute of Food and Drug Safety Evaluation) ;
  • Shin, Hee-Jung (Pharmacological Research Division, Toxicological Evaluation Research Department, National Institute of Food and Drug Safety Evaluation) ;
  • Chung, Hye-Joo (Pharmacological Research Division, Toxicological Evaluation Research Department, National Institute of Food and Drug Safety Evaluation) ;
  • Jeong, Ho-Sang (Pharmacological Research Division, Toxicological Evaluation Research Department, National Institute of Food and Drug Safety Evaluation)
  • Published : 2010.03.31
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Abstract

Mercuric chloride, a model nephrotoxicant was used to elucidate time- and dose- dependent global gene expression changes associated with proximal tubular toxicity. Rat kidney cell lines NRK-52E cells were exposed for 2, 6 and 12 hours and with 3 different doses of mercuric chloride. Cell viability assay showed that mercuric chloride had toxic effects on NRK-52E cells causing 20% cell death (IC20) at $40{\mu}M$ concentration. We set this IC20 as high dose concentration and 1/5 and 1/25 concentration of LC20 were used as mid and low concentration, respectively. Analyses of microarray data revealed that 738 genes were differentially expressed (more than two-fold change and p<0.05) by low concentration of mercuric chloride at least one time point in NRK-52E cells. 317 and 2,499 genes were differentially expressed at mid and high concentration of mercuric chloride, respectively. These deregulated genes showed a primary involvement with protein trafficking (CAV2, CANX, CORO1B), detoxification (GSTs) and immunity and defense (HMOX1, NQO1). Several of these genes were previously reported to be up-regulated in proximal tubule cells treated with nephrotoxicants and might be aid in promoting the predictive biomarkers for nephrotoxicity.

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References

  1. Amin, R.P., Vickers, A.E., Sistare, F., Thompson, K.L., Roman, R.J., Lawton, M., Kramer, J., Hamadeh, H.K., Collins, J., Grissom, S., Bennett, L., Tucker, C.J., Wild, S., Kind, C., Oreffo, V., Davis, J.W.2nd., Curtiss, S., Naciff, J.M., Cunningham, M., Tennant, R., Stevens, J., Car, B., Bertram, T.A., and Afshari, C.A. (2004). Identification of putative gene based markers of renal toxicity. Environ. Health. Perspect. 112, 465-479. https://doi.org/10.1289/ehp.6683
  2. Carranza-Rosales, P., Said-Fernandez, S., Sepulveda-Saavedra, J., Cruz-Vega, D.E., and Gandolfi, A.J. (2005). Morphologic and functional alterations induced by low doses of mercuric chloride in the kidney OK cell line: ultrastructural evidence for an apoptotic mechanism of damage. Toxicology 210, 111-121. https://doi.org/10.1016/j.tox.2005.01.006
  3. Ferguson, M.A., Vaidya, V.S., and Bonventre, J.V. (2008). Biomarkers of nephrotoxic acute kidney injury. Toxicology 245, 182-193. https://doi.org/10.1016/j.tox.2007.12.024
  4. Hansen, C.G., and Nichols, B.J. (2009). Molecular mechanisms of clathrin-independent endocytosis. J. Cell Sci. 122, 1713-1721. https://doi.org/10.1242/jcs.033951
  5. Huang, Q., Dunn, R.T.2nd., Jayadev, S., DiSorbo, O., Pack, F.D., Farr, S.B., Stoll, R.E., and Blanchard, K.T. (2001). Assessment of cisplatin-induced nephrotoxicity by microarray technology. Toxicol. Sci. 63, 196-207. https://doi.org/10.1093/toxsci/63.2.196
  6. Ichimura, T., Hung, C.C., Yang, S.A., Stevens, J.L., and Bonventre, J.V. (2004). Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am. J. Physiol. Renal. Physiol. 286, F552-563. https://doi.org/10.1152/ajprenal.00285.2002
  7. Jonassen, J.A., Cooney, R., Kennington, L., Gravel, K., Honeyman, T., and Scheid, C.R. (1999). Oxalate-induced changes in the viability and growth of human renal epithelial cells. J. Am. Soc. Nephrol. Suppl. 14, S446-S451.
  8. Kilty, C.G., Keenan, J., and Shaw, M. (2007). Histologically defined biomarkers in toxicology. Expert. Opin. Drug. Saf. 6, 207-215. https://doi.org/10.1517/14740338.6.2.207
  9. Lash, L.H., and Zalups, R.K. (1992). Mercuric chloride-induced cytotoxicity and compensatory hypertrophy in rat kidney proximal tubular cells. J. Pharmacol. Exp. Ther. 261, 819-829.
  10. Mi, H., Lazareva-Ulitsky, B., Loo, R., Kejariwal, A., Vandergriff, J., Rabkin, S., Guo, N., Muruganujan, A., Doremieux, O., Campbell, M.J., Kitano, H., and Thomas, P.D. (2005). The PANTHER database of protein families, subfamilies, functions and pathways. Nucl. Acids Res. 33, D284-D288. https://doi.org/10.1093/nar/gki418
  11. Nath, K.A. (2006). Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney Int. 70, 432-443. https://doi.org/10.1038/sj.ki.5001565
  12. Ozaki, N., Matheis, K.A., Gamber, M., Feidl, T., Nolte, T., Kalkuhl, A., and Deschl, U. (2009). Identification of genes involved in gentamicin-induced nephrotoxicity in rats - A toxicogenomic investigation. Exp. Toxicol. Pathol. Epublished.
  13. Perez-Rojas, J., Blanco, J.A., Cruz, C., Trujillo, J., Vaidya, V.S., Uribe, N., Bonventre, J.V., Gamba, G., and Bobadilla, N.A. (2007). Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am. J. Physiol. Renal. Physiol. 292, F131-139.
  14. Prozialeck, W.C., Edwards, J.R., Vaidya, V.S., and Bonventre, J.V. (2009). Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity. Toxicol. Appl. Pharmacol. 238, 301-305. https://doi.org/10.1016/j.taap.2009.01.012
  15. Safirstein, R.L. (2004). Acute renal failure: from renal physiology to the renal transcriptome. Kidney Int. Suppl. 66, S62-S66. https://doi.org/10.1111/j.1523-1755.2004.09110.x
  16. Stacchiotti, A., Morandini, F., Bettoni, F., Schena, I., Lavazza, A., Grigolato, P.G., Apostoli, P., Rezzani, R., and Aleo, M.F. (2009). Stress proteins and oxidative damage in a renal derived cell line exposed to inorganic mercury and lead. Toxicology 264, 215-224. https://doi.org/10.1016/j.tox.2009.08.014
  17. Sundberg, A., Appelkvist, E.L., Dallner, G., and Nilsson, R. (1994). Glutathione transferases in the urine: sensitive methods for detection of kidney damage induced by nephrotoxic agents in humans. Environ. Health Perspect. 102, 293-296. https://doi.org/10.1289/ehp.94102s3293
  18. Takahashi, T., Morita, K., Akagi, R., and Sassa, S. (2004). Heme oxygenase-1: a novel therapeutic target in oxidative tissue injuries. Curr. Med. Chem. 11, 1545-1561. https://doi.org/10.2174/0929867043365080
  19. Tanaka, Y., Aleksunes, L.M., Goedken, M.J., Chen, C., Reisman, S.A., Manautou, J.E., and Klaassen, C.D. (2008). Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity. Toxicol. Appl. Pharmacol. 231, 364-373. https://doi.org/10.1016/j.taap.2008.05.022
  20. Vaidya, V.S., Ferguson, M.A., and Bonventre, J.V. (2008). Biomarkers of acute kidney injury. Annu. Rev. Pharmacol. Toxicol. 48, 463-493. https://doi.org/10.1146/annurev.pharmtox.48.113006.094615
  21. Vaidya, V.S., Ramirez, V., Ichimura, T., Bobadilla, N.A., and Bonventre, J.V. (2006). Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am. J. Physiol. Renal. Physiol. 290, F517-529. https://doi.org/10.1152/ajprenal.00291.2005
  22. Yuen, P.S., Jo, S.K., Holly, M.K., Hu, X., and Star, R.A. (2006). Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses. Physiol. Genomics 25, 375-386. https://doi.org/10.1152/physiolgenomics.00223.2005
  23. Zalups, R.K. (2000). Molecular interactions with mercury in the kidney. Pharmacol. Rev. 52, 113-143.
  24. Zhou, Y., Vaidya, V.S., Brown, R.P., Zhang, J., Rosenzweig, B.A., Thompson, K.L., Miller, T.J., Bonventre, J.V., and Goering, P.L. (2008). Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol. Sci. 101, 159-170. https://doi.org/10.1093/toxsci/kfm260