Effect of the cGMP pathway on AQP2 expression and translocation: potential implications for nephrogenic diabetes insipidus

Nephrol Dial Transplant. 2010 Jan;25(1):48-54. doi: 10.1093/ndt/gfp409. Epub 2009 Aug 8.


Background: Arginine vasopressin (AVP) binding to the V2 receptor (V2R) in renal collecting duct principal cells induces a cAMP signalling cascade resulting in the activation of protein kinase A (PKA), translocation of aquaporin-2 (AQP2) to the apical membrane and an increase in AQP2 expression. Consequently, concentration of urine is initiated. X-linked nephrogenic diabetes insipidus (NDI), characterized by the inability to concentrate urine in response to AVP, is caused by mutations in the V2R gene. Initiation of AQP2 translocation, while circumventing the V2R-cAMP-PKA pathway has been suggested as a putative therapy for these patients. In this respect, the activation of a cAMP-independent and cGMP-dependent pathway for AQP2 membrane insertion by different cyclic guanosine monophosphate (cGMP) pathway activators, such as atrial natriuretic peptide (ANP), l-arginine and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP), has been put forward. However, it is unclear whether they can increase AQP2 expression.

Methods: Mouse cortical collecting duct (mpkCCD) cells were incubated with ANP, l-arginine and 8-Br-cGMP for 2 h and subjected to immunocytochemistry and cell surface biotinylation assays to examine their effect on AQP2 translocation. To test the effect of cGMP pathway activators on AQP2 expression, the mpkCCD cells were treated with dDAVP, ANP and l-arginine for 4 days, or with 8-Br-cGMP for the last day. AQP2 protein levels were determined by immunoblotting.

Results: ANP, l-arginine and 8-Br-cGMP induced the translocation of AQP2 in the mpkCCD cells. However, in contrast to dDAVP, ANP, l-arginine and 8-Br-cGMP did not increase the expression of AQP2.

Conclusions: Our results suggest that while activators of the cGMP pathway are likely beneficial in the treatment of X-linked NDI, their ability to relieve NDI in the patients may be improved when combined with agents stimulating AQP2 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidiuretic Hormone Receptor Antagonists
  • Aquaporin 2 / metabolism*
  • Arginine / pharmacology
  • Arginine Vasopressin / metabolism
  • Atrial Natriuretic Factor / pharmacology
  • Cell Line
  • Cells, Cultured
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • Cyclic GMP / physiology*
  • Diabetes Insipidus, Nephrogenic / drug therapy*
  • Humans
  • Kidney Tubules, Collecting / metabolism*
  • Kidney Tubules, Collecting / pathology
  • Male
  • Models, Animal
  • Morpholines / pharmacology
  • Protein Biosynthesis / physiology*
  • Receptors, Vasopressin / metabolism
  • Signal Transduction / physiology*
  • Spiro Compounds / pharmacology


  • Antidiuretic Hormone Receptor Antagonists
  • Aqp2 protein, mouse
  • Aquaporin 2
  • Morpholines
  • Receptors, Vasopressin
  • Spiro Compounds
  • Arginine Vasopressin
  • 8-bromocyclic GMP
  • Atrial Natriuretic Factor
  • Arginine
  • satavaptan
  • Cyclic GMP