Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamine‑injected mice

Shen,Cheng‑Huang; Wang,Shou‑Tsung; Lee,Ying‑Ray; Liu,Shiau‑Yuan; Li,Yi‑Zhen; Wu,Jiann‑Der; Chen,Yi‑Ju; Liu,Yi‑Wen

doi:10.3892/mmr.2014.2823

Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamine‑injected mice

Authors:
- Cheng‑Huang Shen
- Shou‑Tsung Wang
- Ying‑Ray Lee
- Shiau‑Yuan Liu
- Yi‑Zhen Li
- Jiann‑Der Wu
- Yi‑Ju Chen
- Yi‑Wen Liu
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Affiliations: Department of Urology, Chiayi Christian Hospital, Chiayi 600, Taiwan, R.O.C., Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi 600, Taiwan, R.O.C., Department of Medical Research, Chiayi Christian Hospital, Chiayi 600, Taiwan, R.O.C., Department of Pathology, Chiayi Christian Hospital, Chiayi 600, Taiwan, R.O.C.
Published online on: October 30, 2014 https://doi.org/10.3892/mmr.2014.2823
Pages: 887-895
Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Ketamine is used clinically for anesthesia but is also abused as a recreational drug. Previously, it has been established that ketamine‑induced bladder interstitial cystitis is a common syndrome in ketamine‑abusing individuals. As the mechanisms underlying ketamine‑induced cystitis have yet to be revealed, the present study investigated the effect of ketamine on human urothelial cell lines and utilized a ketamine‑injected mouse model to identify ketamine‑induced changes in gene expression in mice bladders. In the in vitro bladder cell line assay, ketamine induced cytotoxicity in a dose‑ and time‑dependent manner. Ketamine arrested the cells in G1 phase and increased the sub‑G1 population, and also increased the barrier permeability of these cell lines. In the ketamine‑injected mouse model, ketamine did not change the body weight and bladder histology of the animals at the dose of 30 mg/kg/day for 60 days. Global gene expression analysis of the animals' bladders following data screening identified ten upregulated genes and 36 downregulated genes induced by ketamine. A total of 52% of keratin family genes were downregulated, particularly keratin 6a, 13 and 14, which was confirmed by polymerase chain reaction analysis. Keratin 14 protein, one of the 36 ketamine‑induced downregulated genes, was also reduced in the ketamine‑treated mouse bladder, as determined by immunohistochemical analysis. This suggested that cytotoxicity and keratin gene downregulation may have a critical role in ketamine‑induced cystitis.

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1	Domino EF, Chodoff P and Corssen G: Pharmacologic effects of Ci-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 6:279–291. 1965.PubMed/NCBI
2	Sinner B and Graf BM: Ketamine. Handb Exp Pharmacol. 313–333. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ivani G, Vercellino C and Tonetti F: Ketamine: a new look to an old drug. Minerva Anestesiol. 69:468–471. 2003.PubMed/NCBI
4	Domino EF: Taming the ketamine tiger. 1965. Anesthesiology. 113:678–684. 2010.PubMed/NCBI
5	Chu PS, Kwok SC, Lam KM, et al: ‘Street ketamine’-associated bladder dysfunction: a report of ten cases. Hong Kong Med J. 13:311–313. 2007.PubMed/NCBI
6	Shahani R, Streutker C, Dickson B and Stewart RJ: Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 69:810–812. 2007. View Article : Google Scholar : PubMed/NCBI
7	Ng SH, Tse ML, Ng HW and Lau FL: Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases. Hong Kong Med J. 16:6–11. 2010.PubMed/NCBI
8	Tsai TH, Cha TL, Lin CM, et al: Ketamine-associated bladder dysfunction. Int J Urol. 16:826–829. 2009. View Article : Google Scholar : PubMed/NCBI
9	Middela S and Pearce I: Ketamine-induced vesicopathy: a literature review. Int J Clin Pract. 65:27–30. 2011. View Article : Google Scholar
10	Chen CH, Lee MH, Chen YC and Lin MF: Ketamine-snorting associated cystitis. J Formos Med Assoc. 110:787–791. 2011. View Article : Google Scholar
11	Yeung LY, Rudd JA, Lam WP, Mak YT and Yew DT: Mice are prone to kidney pathology after prolonged ketamine addiction. Toxicol Lett. 191:275–278. 2009. View Article : Google Scholar : PubMed/NCBI
12	Meng E, Chang HY, Chang SY, et al: Involvement of purinergic neurotransmission in ketamine induced bladder dysfunction. J Urol. 186:1134–1141. 2011. View Article : Google Scholar : PubMed/NCBI
13	Gu D, Huang J, Shan Z, et al: Effects of long-term ketamine administration on rat bladder protein levels: a proteomic investigation using two-dimensional difference gel electrophoresis system. Int J Urol. 20:1024–1031. 2013.PubMed/NCBI
14	Chuang SM, Liu KM, Li YL, et al: Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder. Neurourol Urodyn. 32:1137–1143. 2013. View Article : Google Scholar : PubMed/NCBI
15	Rigby CC and Franks LM: A human tissue culture cell line from a transitional cell tumour of the urinary bladder: growth, chromosone pattern and ultrastructure. Br J Cancer. 24:746–754. 1970. View Article : Google Scholar : PubMed/NCBI
16	Fogh J, Fogh JM and Orfeo T: One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. 59:221–226. 1977.PubMed/NCBI
17	Mak YT, Lam WP, Lu L, Wong YW and Yew DT: The toxic effect of ketamine on SH-SY5Y neuroblastoma cell line and human neuron. Microsc Res Tech. 73:195–201. 2010.
18	Braun S, Gaza N, Werdehausen R, et al: Ketamine induces apoptosis via the mitochondrial pathway in human lymphocytes and neuronal cells. Br J Anaesth. 105:347–354. 2010. View Article : Google Scholar : PubMed/NCBI
19	Lee ST, Wu TT, Yu PY and Chen RM: Apoptotic insults to human HepG2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondria-caspase protease pathway. Br J Anaesth. 102:80–89. 2009. View Article : Google Scholar
20	Lee CL, Jiang YH and Kuo HC: Increased apoptosis and suburothelial inflammation in patients with ketamine-related cystitis: a comparison with non-ulcerative interstitial cystitis and controls. BJU Int. 112:1156–1162. 2013. View Article : Google Scholar : PubMed/NCBI
21	Harnden P, Eardley I, Joyce AD and Southgate J: Cytokeratin 20 as an objective marker of urothelial dysplasia. Br J Urol. 78:870–875. 1996. View Article : Google Scholar : PubMed/NCBI
22	Oxley JD, Cottrell AM, Adams S and Gillatt D: Ketamine cystitis as a mimic of carcinoma in situ. Histopathology. 55:705–708. 2009. View Article : Google Scholar : PubMed/NCBI
23	Castillo-Martin M, Domingo-Domenech J, Karni-Schmidt O, Matos T and Cordon-Cardo C: Molecular pathways of urothelial development and bladder tumorigenesis. Urol Oncol. 28:401–408. 2010. View Article : Google Scholar : PubMed/NCBI
24	Coulombe PA, Kerns ML and Fuchs E: Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility. J Clin Invest. 119:1784–1793. 2009. View Article : Google Scholar : PubMed/NCBI
25	Arifi M, Arifi S, Demni K, et al: Genitourinary complications as initial presentation of inherited epidermolysis bullosa. Afr J Paediatr Surg. 8:72–74. 2011. View Article : Google Scholar : PubMed/NCBI
26	Alam H, Sehgal L, Kundu ST, Dalal SN and Vaidya MM: Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells. Mol Biol Cell. 22:4068–4078. 2011. View Article : Google Scholar : PubMed/NCBI
27	Mercurio AM: Laminin receptors: achieving specificity through cooperation. Trends Cell Biol. 5:419–423. 1995. View Article : Google Scholar : PubMed/NCBI