Aquaporin-4-Mediated Water Permeability Rescues Aquaporin-3 Deficiency Caused Nephrogenic Diabetes Insipidus

Aim

The aim of this study was to determine whether water or solute transport plays a critical role in AQP3-mediated urine concentrating ability, using AQP3 knockout (AQP3-KO) mice and a novel mouse model in which the AQP3 gene coding region is replaced with AQP4 cDNA (AQP4-KI).

Methods

AQP3-KO and AQP4-KI mice were characterized using Western blot and immunofluorescence to confirm the absence of AQP3 and the in situ replacement of AQP4. Urinary output, osmolality and urea concentration were measured in mouse models under various conditions, including water deprivation, acute urea loading and high protein intake.

Results

AQP3-KO mice exhibited a significantly increased daily urine output (6 times that in wild-type mice) and reduced urinary osmolality (< 1000 mOsm/kg), with a marked inability to concentrate urea and osmolality in response to water deprivation, urea loading or high protein intake. In contrast, AQP4-KI mice showed restoration of urine output, urinary osmolality and urea concentration, approaching wild-type levels.

Conclusion

In situ replacement of AQP3 with AQP4 restores AQP3-mediated water permeability in the renal collecting duct, rescuing the nephrogenic diabetes insipidus (NDI) phenotype in AQP3-deficient mice. This study provides evidence that AQP3-mediated water permeability plays a crucial role in the renal urine concentrating mechanism.