Role of water channels in fluid transport studied by phenotype analysis ofaquaporin knockout mice

Aquaporin-type water channels are expressed widely in mammalian tissues, pa rticularly in the kidney, lung, eye and gastrointestinal tract. To define t he role of aquaporins in organ physiology, we have generated and analysed t ransgenic mice lacking aquaporins (AQP) 1, 3, 4 and 5. Multiple phenotype a bnormalities were found in the null mice. For example, in kidney, deletion of AQP1 or AQP3 produced marked polyuria whereas AQP4 deletion produced onl y a mild concentrating defect. Deletion of AQP5, the apical membrane water channel in the salivary gland, caused defective saliva production. Deletion of AQP1 or AQP5, water channels in lung endothelia and epithelia, resulted in a 90% decrease in airspace-capillary water permeability. In the brain, deletion of AQP4 conferred marked protection From brain swelling induced by acute water intoxication and ischaemic stroke. The general paradigm that h as emerged from these phenotype studies is that aquaporins facilitate rapid near-isosmolar transepithelial fluid absorption/secretion, as well as rapi d vectorial water movement driven by osmotic gradients. However, we have fo und many examples in which the tissue-specific expression of an aquaporin i s not associated with any apparent phenotypic abnormality. The physiologica l data on aquaporin null mice suggest the utility of aquaporin blockers and aquaporin gene replacement in selected human diseases.