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First published online May 15, 2009
Journal of Experimental Biology 212, 1707-1715 (2009)
Published by The Company of Biologists 2009
doi: 10.1242/jeb.024125

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Aquaporins: translating bench research to human disease

A. S. Verkman

Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA

View larger version (33K): [in this window] [in a new window]   Fig. 1. Roles of aquaporins (AQPs) in mammalian physiology based on their water transport function. (A) Reduced transepithelial water permeability in kidney collecting duct impairs urinary-concentrating ability by impairing osmotic equilibration of luminal fluid. Numbers represent hypothetical fluid osmolalities. (B) Reduced water permeability in an epithelium, such as salivary gland, impairs active, near-isosmolar fluid secretion by slowing osmotic water transport into the acinar lumen, resulting in the secretion of a reduced volume of a hypertonic fluid. (C) Routes of water movement into and out of the brain. Water movement shown through AQP4-expressing glial cells at glia limitans and the blood–brain barrier. (D) Proposed mechanism of AQP-facilitated cell migration, showing water entry into protruding lamellipodia in migrating cells. (E) AQP4-dependent neuroexcitation, showing AQP4-facilitated water transport in glial cells, which communicate with neurons through changes in extracellular space volume and K+ concentration.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Roles of AQPs in mammalian physiology based on their glycerol transport function. (A) Reduced glycerol content in epidermis and stratum corneum in skin in AQP3 deficiency, accounting for reduced skin hydration. (B) Proposed mechanism of AQP3-facilitated cell proliferation involving reduced cellular glycerol and consequent reduced ATP energy and biosynthesis. (C) Proposed mechanism for adipocyte hypertrophy in AQP7 deficiency, showing impaired AQP7-dependent glycerol escape from adipocytes resulting in cellular glycerol and triglyceride accumulation. Glycerol 3-P, glycerol 3-phosphate; TG, triacylglycerol; FFA, free fatty acid.

View larger version (10K): [in this window] [in a new window]   Fig. 3. Erythrocyte osmotic lysis assay for discovery of aquaporins and urea transport inhibitors. Erythrocytes expressing water and urea channels (AQP1 and UT-B) are preloaded with urea or a urea analog, such as acetamide. Following replacement of the external buffer with urea/acetamide-free hypo-osmolar solution, water entry results in cell swelling, which is limited by UT-B-mediated urea/acetamide efflux. Under optimized assay conditions, UT-B-facilitated urea/acetamide produces partial osmotic lysis (middle), whereas AQP1 inhibition slows water influx, preventing lysis (top), and UT-B inhibition impairs urea/acetamide exit resulting in greater lysis (bottom).

View larger version (77K): [in this window] [in a new window]   Fig. 4. AQP2 transgenic mouse models of nephrogenic diabetes insipidus. (A) Gene targeting strategy for introducing the T126M mutation into AQP2. Homologous recombination results in replacement of the indicated segment (thick line) of the AQP2 gene by a 1.8 kb neomycin selection cassette (neo) flanked by loxP sites. PGK-tk, phosphoglycerate promoter–thymidine kinase gene. (B, left) Photograph of mice of indicated genotypes at 5 days after birth. +/+, wild-type; Hetero, heterozygote; T126M, AQP2-T126M mutant. (B, right) Immunoblot of kidney homogenates. (C) Urine osmolality in tamoxifen-treated wild-type mice (WT, open circles) and AQP2 floxed knock-out mice (filled circles) given free access to food and water. Arrows indicate tamoxifen injections. (D) Twenty-four hour urine output in untreated (left) and tamoxifen-treated (right) wild-type and AQP2 knock-out (`flox') mice (arrows indicate urine level).

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