Dissecting the Roles of Aquaporins in Renal Pathophysiology Using Transgenic Mice

https://doi.org/10.1016/j.semnephrol.2008.03.004Get rights and content

Summary

Transgenic mice lacking renal aquaporins (AQPs), or containing mutated AQPs, have been useful in confirming anticipated AQP functions in renal physiology and in discovering new functions. Mice lacking AQPs 1-4 manifest defects in urinary concentrating ability to different extents. Mechanistic studies have confirmed the involvement of AQP1 in near-isosmolar fluid absorption in the proximal tubule, and in countercurrent multiplication and exchange mechanisms that produce medullary hypertonicity in the antidiuretic kidney. Deletion of AQPs 2-4 impairs urinary concentrating ability by reduction of transcellular water permeability in the collecting duct. Recently created transgenic mouse models of nephrogenic diabetes insipidus produced by AQP2 gene mutation offer exciting possibilities to test new drug therapies. Several unanticipated AQP functions in kidney have been discovered recently that are unrelated to their role in transcellular water transport. There is evidence for involvement of AQP1 in kidney cell migration after renal injury, of AQP7 in renal glycerol clearance, of AQP11 in prevention of renal cystic disease, and possibly of AQP3 in regulation of collecting duct cell proliferation. Future work in renal AQPs will focus on mechanisms responsible for these non–fluid-transporting functions, and on the development of small-molecule AQP inhibitors for use as aquaretic-type diuretics.

Section snippets

AQPs and Urinary Concentrating Function

A major and anticipated role of AQPs in kidney is in water transport across kidney tubules and vasa recta for the formation of a concentrated urine in the antidiuretic kidney. Deletion of AQP1 and/or AQP3 in mice results in marked polyuria, as seen in 24-hour urine collections (Fig. 1B).15, 16Fig. 1C summarizes urine osmolalities before and after a 36-hour water deprivation. Urinary osmolality in AQP1 null mice is low and does not increase with water deprivation, resulting in severe

Mouse Models of AQP2 Gene Mutation/Deletion

Mutations in the AQP2 water channel produce the rare genetic disorder of nephrogenic diabetes insipidus (NDI). Some AQP2 mutations produce non–X-linked NDI by a recessive mechanism, which involves defective mutant AQP2 protein folding/function; a few AQP2 mutations produce a dominant form of NDI resulting from endoplasmic reticulum (ER)/Golgi interactions between wild-type and mutant AQP2 that prevent plasma membrane targeting of wild-type AQP2 (reviewed by Robben et al23). We have been

AQP7 and Renal Glycerol Clearance

AQP7 is expressed selectively in the apical membrane of epithelial cells in the relatively short S3 straight segment of the proximal tubule. AQP7, similar to AQP3, is an aquaglyceroporin that transports both water and glycerol, whereas most of the other AQPs primarily transport water. A curious phenotype was found for mice lacking AQP7.32 Although urinary concentrating function was intact, there was increased urinary glycerol clearance. Urinary glycerol concentration in AQP7 null mice was

AQP11 and Renal Cystic Disease

AQP11 has a somewhat different amino acid sequence from other AQPs in that it lacks 1 of the 2 conserved asparagine-proline-alanine motifs. Whether AQP11 functions as a water channel has been debated, although a recent report showed a small increase in water permeability in liposomes reconstituted with recombinant AQP11.33 In kidney, AQP11 appears to be expressed in intracellular vesicles in the proximal tubule,34 although available antibodies are limited in their specificity. AQP11 null mice

AQPs and Cell Migration

As reviewed recently,35 we discovered a novel cellular role for AQPs in cell migration, which initially was shown in endothelial cells and various transfected cells,36 and subsequently found in brain astroglial cells,37 tumor cells,38 corneal epithelial cells,39 and epidermal cells.40 The general finding, in multiple cell types, is that AQP expression increases cell water permeability and migration toward a chemotactic stimulus, with little or no effect on cell size, adherence, or other

A Role for AQP3 in Epithelial Cell Proliferation

New evidence from extrarenal tissues supports a role for AQP3 in cell proliferation that may be of relevance in kidney collecting duct epithelium, where AQP3 is strongly expressed in the basolateral membrane. AQP3 null mice manifest defective cell proliferation in multiple tissues where AQP3 is normally expressed. At the ocular surface, where AQP3 is expressed in corneal and conjunctival surface epithelium, AQP3 deletion results in delayed restitution of the corneal surface after denudation,

Role of Aquaporins in Peritoneal Fluid Transport

The peritoneal cavity is lined by a membranous barrier that provides a large surface for fluid movement between peritoneal capillaries and the peritoneal cavity. Although the peritoneal cavity normally contains little fluid, marked ascites can accumulate in conditions associated with reduced serum oncotic pressure, increased portal venous pressure, or peritoneal cavity inflammation/infection. The large peritoneal surface is exploited in peritoneal dialysis, where water and solutes are extracted

Summary and Future Directions

Renal phenotype studies of AQP knockout mice have confirmed the predicted roles of AQPs in the urinary concentrating mechanism, and have suggested potential new roles of AQPs in renal cell migration and proliferation, glycerol clearance, and cystogenesis. Several transgenic mouse models of AQP2 mutations are now available for testing of potential drug therapies. Although NDI is an extremely rare disorder and therefore unlikely to be a candidate for development of new chemical entity drugs,

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      However, a large amount of the glycerol that enters the kidney proximal tubule cells is used in the gluconeogenesis process, which contributes up to 20–25% of the whole-body glucose production [111,112]. There is no need to emphasize the importance of aquaporins in the urinary concentration function: the osmotic water transport across the tubule epithelium is an AQP-facilitated mechanism (for reviews, see [15,113,114]). So far, eight AQPs have been identified in the mammal kidney: AQP1, 2, 3, 4, 6, 7, 8, 11, each characterized by a specific cellular or subcellular localization [15].

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    Supported by grants DK35124, DK72517, EY13574, EB00415, HL59198, and HL73856 from the National Institutes of Health, and Research Development Program and Drug Discovery grants from the Cystic Fibrosis Foundation.

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