Role of aquaporin water channels in kidney function studied using transgenic mice |
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Authors: | A S Verkman J Li T Ma B Yang |
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Institution: | (1) Departments of Medicine and Physiology, 1246 Health Sciences East Tower, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-0521, USA Tel. +1-415-476-8530; Fax +1-415-665-3847 e-mail: verkman@itsa.ucsf.edu; http://www.ucsf.edu/verklab, US |
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Abstract: | Several aquaporin (AQP) water transporting proteins are expressed in mammalian kidney: AQP1 in plasma membranes of proximal
tubule, thin descending limb of Henle, and descending vasa recta; AQP2 in collecting duct luminal membrane; AQP3 and AQP4
in collecting duct basolateral membrane; AQP6 in intercalated cells; and AQP7 in the S3 segment of proximal tubule. To define
the role of aquaporins in renal physiology, we have generated and characterized transgenic null mice deficient in AQP1, AQP3,
and AQP4, individually and in combinations, as well as AQP2 mutant mice, in which the T126M mutation causing human nephrogenic
diabetes insipidus was introduced. AQP1-deficient mice are polyuric and unable to concentrate their urine in response to water
deprivation or vasopressin administration. AQP1 deletion greatly reduces osmotic water permeability in proximal tubule, thin
descending limb of Henle, and descending vasa recta, resulting in defective proximal tubule fluid absorption and medullary
countercurrent exchange. Mice lacking AQP3 have low basolateral membrane water permeability in cortical collecting duct and
excrete large quantities of dilute urine. Mice lacking AQP4 have low water permeability in inner medullary collecting duct,
but manifest only a mild defect in maximum urinary concentrating ability. These data, taken together with phenotype analyses
of brain, lung, and gastrointestinal organs, support the paradigm that aquaporins facilitate rapid near-isosmolar transepithelial
fluid absorption/secretion, as well as rapid vectorial water movement driven by osmotic gradients. The renal phenotype data
in aquaporin knockout mice suggests the utility of aquaporin blockers as novel aquaretic-diuretic agents.
Received: March 19, 2001 / Accepted: March 22, 2001 |
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Keywords: | Water transport AQP Urinary concentrating mechanism |
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