Cyclophosphamide-induced Down-Regulation of Uroplakin II in the Mouse Urinary Bladder Epithelium is Prevented by S-Allyl Cysteine.

The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP-induced HC. In this study, we studied the modulatory effect of the thiol-rich compound S-allyl cysteine (SAC) on the mRNA level of uroplakin II by real-time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)-induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP-induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol-rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP-induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium.

Intravesical epinephrine preserves uroplakin II expression in urinary bladder from cyclophosphamide-induced rat cystitis.

We investigated the attenuated effect of intravesical epinephrine (EPI) on uroplakin II (UPII) expression in cyclophosphamide (CYP)-induced rat cystitis. Sixty-eight Sprague-Dawley female rats were divided into one negative control group (GI) and five intraperitoneally CYP (150 mg CYP/kg)-injected groups (GII-VI) consisting of a positive control group (GII), three groups (GIII-V) with retaining intravesically instillated ameliorating agents for 90 min by urethral ligation until sacrifice, and one group (GVI) with freely voiding after intravesical EPI instillation. The retention groups were further classified into null-treated- (GIII), EPI- (GIV), and vehicle group (GV). All rats were euthanized 24 h after CYP injection. The UPII and α1-adrenergic receptors (AR) levels were measured with real-time polymerase chain reaction (RT-PCR) method and the morphological changes were also evaluated. CYP induced severe cystitis and decreased vesical UPII mRNA level. The EPI-treated groups had showed attenuation effects against submucosal edema and hemorrhage, and preserved UPII expression. Concurrently, intravesical EPI resulted in a significant preservation of both subtypes of α1A- and α1B AR expressions, which was well correlated with the hemostatic pattern in the samples. The obstructed and null-treated group (GIII) revealed severe cystitis and maximally decreased UPII levels, and the diluting effect of vehicle (GV) on CYP toxicity was insignificant on UPII preservation. The UPII level of RT-PCR was well correlated with the UPII immunohistological expression and their morphological changes. Intravesical instillation of EPI preserves UPII expression and attenuates the toxic responses in the bladder in CYP-induced rat cystitis.