Urothelial cells produce hydrogen peroxide through the activation of Duox1

Hydrogen peroxide (H2O2) has important messenger and effector functions in the plant and animal kingdom. Phagocytes produce H2O2 to kill pathogens, and epithelial cells of large airways have also been reported to produce H2O2 for signaling and host defense purposes. In this report, we show for the first time that urothelial cells produce H2O2 in response to a calcium signal. Using a gene-deficient mouse model we also demonstrate that H2O2 is produced by the NADPH oxidase Duox1, which is expressed in the mouse urothelium. In contrast, we found no evidence for the expression of lactoperoxidase, an enzyme that has been shown to cooperate with Duox enzymes. We also found that specific activation of TRPV4 calcium channels elicits a calcium signal and stimulates H2O2 production in urothelial cells. Furthermore, we detected altered pressure responses in the urinary bladders of Duox1 knockout animals. Our results raise the possibility that mechanosensing in epithelial cells involves calcium-dependent H2O2 production similar to that observed in plants.