2004 Global Researcher Conference Proceeding
April 09 - 11, 2004
| Conference: | 2004 Global Researcher Conference |
|---|---|
| Title: | Novel Roles of Aquaporin Water Channels Revealed by Phenotype Analysis of Knockout Mice |
| Authors: | Verkman, Alan S.; Binder, David; Da, Tong; Levin, MH; Hara, M.; Ma, Tonghui; Manley, Geoffery T.; Papadopolous, Maria; Thiagarajah, J.; Yang, Baoxue |
| Institutions: | University of California, S.F., U.C. S.F., University of California, UCSF, University of California, San Francisco |
Prior work from our lab has defined in mice the roles of AQP1, AQP3 and AQP4 in the urinary concentrating mechanism, as well as effects of targeted replacement of the mouse AQP2 gene by a mutant AQP2 causing NDI in humans. Recent work has revealed several novel phenotypes in aquaporin deficiency. AQP3 gene deletion produced relatively dry skin, with 2-3 fold reduced water content in stratum corneum and defective skin elasticity and biosynthetic functions. Analysis of skin composition and morphology indicated reduced glycerol content in stratum corneum and epidermis as the specific defect in AQP3 deficiency. Together with data showing correction of the skin abnormalities after systemic glycerol administration, we conclude that reduced epidermal glycerol transport in AQP3 null mice produced the skin abnormalities. Several lines of evidence suggest that aquaporins play a role in rapid neural signal transduction, possibly by modulation of extracellular space (ECS) volume and ionic content. Mice lacking AQP4 have reduced light- and sound- evoked potential responses, and elevated seizure threshold and prolonged seizure duration after hippocampal stimulation. To investigate the role of the ECS in this response, we developed a cortical surface photobleaching method to quantify fluorescent probe diffusion in the ECS. FITC-dextran diffusion was significantly enhanced in brain cortex of AQP4 null mice, suggesting an expanded ECS. Additional phenotype observations in AQP4 deficient mice include reduced clearance of excess brain water in models of vasogenic brain swelling including brain tumor, and neuroprotection of retina and brain tissue after transient ischemia. The multiplicity of phenotypes revealed in aquaporin-deficient mice suggests specific clinical applications of small-molecule aquaporin inhibitors and enhancers.
Verkman, et al., developed a line of mice lacking the various aquaporin (AQP) genes. Mice lacking AQP3 have relatively dry skin due to reduced epidermal glycerol transport. Mice lacking AQP4 have reduced light and sound evoked responses, an elevated seizure threshold and prolonged seizure duration after hippocampal stimulation. The researchers speculated that extracellular space (ECS) volume might play a role in this. Their research suggests that mice lacking the AQP4 gene have expanded ECS. Verkman suggests that the development of AQP inhibitors and enhancers will contribute to treatment of disorders involving AQP.