Physiological importance of aquaporin water channels

Aquaporins (AQP) are a family of at least ten homologous water transporting proteins in mammals that are expressed in many epithelial, endothelial and other tissues. Abnormalities in humans and mice lacking AQPs provide direct evidence for their physiological importance. Humans lacking AQP1 or AQP2 manifest polyuria with defective urinary concentrating ability and humans with mutations in MIP (AQPO) develop cataracts. Transgenic knockout mice lacking AQP1 or AQP3 are also remarkably polyuric, and knock-in mice expressing a mutant AQP2 have severe nephrogenic diabetes insipidus resulting in impaired neonatal survival. Other interesting phenotypes in AQP knockout mice include reduced pain sensation, reduced intraocular pressure, defective corneal fluid transport and impaired dietary fat processing (AQP1), dry skin (AQP3), protection from brain swelling and impaired hearing/vision (AQP4), and reduced fluid secretion by salivary and airway submucosal glands (AQP5). However, many phenotype studies were negative, such as normal airway/lung and skeletal muscle function despite AQP expression, indicating that tissue-specific aquaporin expression does not indicate physiological significance. The general paradigm from studies on transgenic mouse models of AQP deletion is that AQPs facilitate rapid near-isosmolar transepithelial fluid absorption/secretion, as well as rapid vectorial water movement driven by osmotic gradients. The transgenic mouse studies suggest that aquaporin inhibitors may have clinical indications as diuretics and in the treatment of cerebral edema, elevated intraocular pressure, and other conditions of abnormal fluid homeostasis.