title: Ketamine-induced ulcerative cystitis and bladder apoptosis involve oxidative stress mediated by mitochondria and the endoplasmic reticulum.
abstract: Ketamine abusers develop severe lower urinary tract symptoms. The major aims of the present study were to elucidate ketamine-induced ulcerative cystitis and bladder apoptosis in association with oxidative stress mediated by mitochondria and the endoplasmic reticulum (ER). Sprague-Dawley rats were distributed into three different groups, which received normal saline or ketamine for a period of 14 or 28 days, respectively. Double-labeled immunofluorescence experiments were performed to investigate tight junction proteins for urothelial barrier functions. A TUNEL assay was performed to evaluate the distribution of apoptotic cells. Western blot analysis was carried out to examine the expressions of urothelial tight junction proteins, ER stress markers, and apoptosis-associated proteins. Antioxidant enzymes, including SOD and catalase, were investigated by real-time PCR and immunofluorescence experiments. Ketamine-treated rats were found to display bladder hyperactivity. This bladder dysfunction was accompanied by disruptions of epithelial cadherin- and tight junction-associated proteins as well as increases in the expressions of apoptosis-associated proteins, which displayed features of mitochondria-dependent apoptotic signals and ER stress markers. Meanwhile, expressions of mitochondria respiratory subunit enzymes were significantly increased in ketamine-treated bladders. Conversely, mRNA expressions of the antioxidant enzymes Mn-SOD (SOD2), Cu/Zn-SOD (SOD1), and catalase were decreased after 28 days of ketamine treatment. These results demonstrate that ketamine enhanced the generation of oxidative stress mediated by mitochondria- and ER-dependent pathways and consequently contributed to bladder apoptosis and urothelial lining defects. Such oxidative stress-enhanced bladder cell apoptosis and urothelial barrier defects are potential factors that may play a crucial role in bladder overactivity and ulceration.
authors.affiliation: Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Keh-Min
authors.initials: KM
authors.lastname: Liu
authors.affiliation: Translational Research Center, Cancer Center, Department of Medical Research, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Shu-Mien
authors.initials: SM
authors.lastname: Chuang
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Long
authors.affiliation: Department of Urology, Chi-Shan Hospital, Department of Health, Executive Yuan, Kaohsiung, Taiwan; Graduate Institute of Medical Science, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Yi-Lun
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Chao-Chuan
authors.initials: CC
authors.lastname: Wang
authors.affiliation: National Museum of Marine Biology and Aquarium, Pingtung, Taiwan; Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung, Taiwan;
authors.forename: Mei-Chin
authors.initials: MC
authors.lastname: Lu
authors.affiliation: Department of Parasitology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Rong-Jyh
authors.initials: RJ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Science, Kaohsiung Medical University, Kaohsiung, Taiwan;
authors.forename: Jian-He
authors.initials: JH
authors.lastname: Lu
authors.affiliation: Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan;
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Jang
authors.affiliation: Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; and Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Wen-Jeng
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; and.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Ho
authors.affiliation: Graduate Institute of Medical Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; and Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan juanuro@gmail.com.
authors.forename: Yung-Shun
authors.initials: YS
authors.lastname: Juan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003556:Cystitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D007649:Ketamine; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014456:Ulcer / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001743:Urinary Bladder / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014563:Urodynamics; D019459:Urothelium / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D007649:Ketamine
keywords: apoptosis; endoplasmic reticulum; ketamine; mitochondria; oxidative stress; urothelial barrier