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

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.