Aquaporins permeability to hydrogen peroxide may control oxidative stress

Transmembrane water channel proteins, known as aquaporins (AQPs), play a pivotal role in many biological processes including volume regulation, cell migration and proliferation, and adipocyte metabolism. Recently, it has been demonstrated the involvement of some AQPs, known as “peroxiporins”, in the transport of hydrogen peroxide (H2O2). H2O2 is the most abundant and stable reactive oxygen species (ROS) in living cells and H2O2 can have different effects depending on its concentration. Physiological levels of H2O2 induce positive adaptive responses acting as second messenger, while excessive levels provoke negative effects as apoptosis and cell death. Since AQPs allow the diffusion of H2O2 across plasma membranes to the extracellular fluid, they have been considered as a possible ROS scavenging mechanism. Until now, AQP1, 3, 5, 8, 9 and 11 are the mammalian AQPs involved in H2O2 diffusion. This project aims to understand the mechanism of AQPs as peroxiporins in mediating H2O2 diffusion through cellular plasma membrane. The guiding thread of this thesis was, on the one hand, the analysis of the role of peroxiporins in some pathophysiological conditions and, on the other, the identification and characterization of new gating modulators. In particular this thesis aimed: 1. to investigate the negative role of human Papillomavirus (HPV) infection on the aquaporin-mediated hydrogen peroxide elimination which affects human sperm functioning; 2. to clarify AQPs/peroxiporins involvement in malignant pleural mesothelioma progression (MPM); 3. to identify and characterize new aquaporin modulators to counteract the oxidative stress. As a whole, AQPs permeability alteration (and sensitivity to oxidative stress) in HPV infection and in MPM seems to reduce the fertility of sperm cells and make MPM cells resistant to conventional chemotherapy, respectively. The possibility to modify the gating of the AQPs and ROS scavenging opens to new therapeutic strategies for the treatment of debilitating diseases involving oxidative stress namely neurodegenerative diseases and cancer.