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.