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AND OBJECTIVES: Recognition of the urothelium as a new sensory structure has generated intense interest in identifying its functional regulators, in particular, the pathological mediators. Oxidative stress is a fundamental pathological mediator. ROS generating enzyme Nox is of particular importance as it is the only enzyme in the body that produces ROS as its sole function and can therefore be targeted without compromising normal biochemical oxidation. Our recent demonstration that bladder urothelium is a major source of superoxide in the body, originated from Nox enzymes, has opened a new scope of exploration of this enzyme as the urotheliumspecific drug target. This study aimed to dissect the functional subtypes in the urothelium and bladder tissue. METHODS: C57BL/6J mice were euthanized. Bladder mucosa and smooth muscle were isolated under microscopic guidance. Lucigenin-enhanced chemiluminescence quantified superoxide production in live tissue. Immunofluorescence staining and Western blot determined Nox subtype expressions. RESULTS: NADPH-dependent and Tiron (superoxide scavenger)-sensitive superoxide production in bladder mucosa was reduced by Nox1 specific inhibitor NoxA1ds (5mM) to 85.4 5.1 % of control (mean SEM; n1⁄426, p<0.01). Nox 2 specific inhibitor GSK2759039 (1mM) reduced the superoxide production to 72.9 8.4 % of control (n1⁄412, p<0.01). In a further set of experiments with combined application of inhibitors, a combination of Nox1 inhibitor NoxA1ds (5mM) and Nox2 inhibitor GSK2759039 (1mM) reduced the superoxide production to 68.0 14.6 % of control (n1⁄411, p<0.05), while addition of Nox1/Nox4 dual selective inhibitor GSK137831 (2mM) in the presence of the above two inhibitors reduced the superoxide production to 53.3 6.7% of control (p<0.01), revealing additional Nox4-selective inhibition. Similar inhibitory effects were observed in detrusor smooth muscles although the control superoxide levels were much lower in the smooth muscle. Immunostaining and Western blot also identified Nox1, Nox2 and Nox4 subtype expressions in the bladder mucosa and smooth muscle (n1⁄45-7). CONCLUSIONS: These data show for the first time that the functional subtypes of Nox enzymes in the urothelium are Nox1, Nox2, and also Nox4, consistent with protein expressions. The finding demonstrates the importance of these subtypes in regulating urothelial and bladder function in oxidative stress-associated pathologies and also provides quantitative information on targeting these subtypes in controlling oxidative stress in bladder inflammation and sensory dysfunction.

PD55-11 IDENTIFYING THE FUNCTIONAL SUBTYPES OF NADPH OXIDASES (NOX) FROM THE UROTHELIUM: IMPLICATION FOR ROS-CONTROLLING TARGETS