More than 190 disease-causing mutations of V2 vasopressin receptor (AVPR2) have been identified in patients with X-linked nephrogenic diabetes insipidus (NDI). About half of the mutations lead to a loss or truncation of the receptor protein whereas missense mutations present a variety of functional alterations such as reduced binding and signaling abilities and improper cell surface trafficking. To date, the therapy of NDI focuses mainly on treating clinical symptoms with thiazide diuretics often in combination with amiloride and indomethacin. Because current therapeutic protocols are of limited efficiency and are often accompanied by adverse effects, alternative approaches including application of potent agonists and gene therapeutic approaches are under investigation. For example, several therapeutic approaches aimed at modulating chaperone function. These attempts are based on the findings that most inactivating missense mutations in G-protein-coupled receptors (GPCR) lead to receptor retention in the cell interior. Treatment of cells expressing certain mutant GPCR with ligands, which are known to stabilize the receptor protein in its native conformation, resulted in the correct processing of mutant GPCR proteins and their proper delivery to the plasma membrane, thus restoring GPCR function. About 10% of NDI-causing mutations represent nonsense mutations which lead to the generation of truncated, non-functional receptor proteins. Recent in vitro and in vivo studies have shown that aminoglycoside antibiotics can suppress premature stop codons in the AVPR2, thereby permitting protein translation to continue to the normal end of the coding sequence. Animal models for NDI are now important tools to investigate the feasibility of new approaches and may help to gain more insights into the NDI pathomechanism. Thus, recent animal data implicate an increased bicarbonate and sodium re-uptake in the kidney of AVPR2-deficient mice and provide new mechanistic views of the development of hypernatremia in NDI patients and of the therapeutic benefit from thiazide diuretics.
01 - 05 Apr 2006
European Society of Endocrinology