Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1.
Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Department of Urology, Henan Provincial People's Hospital, Zhengzhou, China; and.
Junpeng
J
Wang
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Yang
Y
Chen
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Di
D
Gu
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Guihao
G
Zhang
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Jiawei
J
Chen
Department of Urology, Henan Provincial People's Hospital, Zhengzhou, China; and.
Jie
J
Zhao
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China; doctorwupeng@gmail.com.
Peng
P
Wu
D000700:Analgesics / Q000009:adverse effects*; D000818:Animals; D002460:Cell Line; D003556:Cystitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D007649:Ketamine / Q000009:adverse effects*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders / Q000150:complications* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D014554:Urination / Q000187:drug effects; D014563:Urodynamics
D000700:Analgesics; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D007649:Ketamine
EMT; cystitis; cystometry; detrusor smooth muscle; fibrosis; ketamine; transforming growth factor-ß1; urothelium