Dissecting the Roles of Aquaporins in Renal Pathophysiology Using Transgenic Mice

Abstract

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 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 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 following 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.

Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect

“…19 Renal AQP7 is responsible for reabsorption of glycerol at the renal proximal tubules in coordination with AQP3. 30,31 All the homozygous carriers of G264V AQP7 in our study had hyperglyceroluria, whereas no glycerol loss was present in the heterozygous parents. The hypothesis that this mutation has functional relevance was earlier supported by the findings of Kondo et al, 20 who could not show any association between the presence of the mutation and the occurrence of obesity or type 2 diabetes; however, they did find the first homozygous G264V subject with impaired plasma glycerol release from fat tissue after exercise tests, although urine glycerol levels were not determined.…”

“…30,31 No mutations were detected in AQP3 and AQP9. In the AQP7 gene, a homozygous nucleotide substitution (G to T in exon 8) was detected in all three index cases, converting glycine into valine at codon 264 (G264V) in the sixth transmembrane domain of the protein (Figure 1b).…”

A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus

“…Moreover, immunoblotting studies showed that renal AQP2 and AQP3 expression levels were drastically reduced (by ~70%-80%) in V2R-KO mice. The kidney collecting duct AQP2 and AQP3 water channels are known to play a key role in mediating AVP-dependent water reabsorption (4,(30)(31)(32). These observations strongly suggest that human XNDI is also associated with pronounced decreases in AQP2 and AQP3 expression levels.…”

Aquaporins at a glance

“…Osmotic water transport by the thin descending limb of Henle, where AQP1 is highly expressed, is required for the countercurrent multiplication mechanism to generate concentrated urine (Chou et al, 1999). Water transport across the collecting duct epithelium involves vasopressin-regulated AQP2 trafficking to the apical plasma membrane, as mentioned above, with constitutively high water permeability of the basolateral membrane conferred by the constitutive expression of AQP3 and AQP4 (Verkman, 2008;Noda et al, 2010).…”