Conditional V2 Vasopressin Receptor Mutant Mice as a Model to Study X-linked Nephrogenic Diabetes Insipidus (XNDI)


X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. This technology provides a unique and viable animal model of XNDI. NIH investigators have generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin.

Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology. These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI.

Inventors:

Jurgen Wess (NIDDK)  ➽ more inventions...


Intellectual Property:
Research Tool -- patent protection is not being pursued for this technology

Publications:
Li JH, Chou CL, Li B, Gavrilova O, Eisner C, Schnermann J, Anderson SA, Deng CX, Knepper MA, Wess J. A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus. J Clin Invest. 2009 Oct 1;119(10):3115-3126. PubMed: 19729836

Collaboration Opportunity:

The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, Molecular Signalling Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact Dr. Jurgen Wess at jwess@helix.nih.gov for more information.


Licensing Contact:
Cristina Thalhammer-Reyero, Ph.D., M.B.A.
Email: cristina.thalhammer-reyero@nih.gov
Phone: 301-435-4507

OTT Reference No: E-174-2009/0
Updated: Jul 12, 2017