A low affinity vasopressin v₂-receptor in inherited nephrogenic diabetes insipidus

Congenital nephrogenic diabetes insipidus (NDI) is an X-linked inherited disorder characterized by renal resistance to the antidiuretic hormonal action of vasopressin. This study describes the molecular basis of nephrogenic diabetes insipidus in a dog family. Kidney membranes prepared from NDI-affected male huskies were examined for vasopressin binding and response. Compared to membranes from unaffected canines, those from the kidney inner medulla of NDI-dogs possessed normal V₂-receptor numbers, but with 10-fold lower affinity for [Arg⁸] vasopressin (AVP). Adenylate cyclase stimulation by AVP in contrast to that by forskolin or GTP-analogues was similarly reduced in a dose responsive manner. The NDI-affected dogs showed antidiuretic responses to very high doses of V₂-specific agonists, consistent with their possessing V₂-receptors of lower affinity. Prolonged treatment with V₂-agonists, 1-deamino [D-Arg⁸] VP (dDAVP) and 1-deamino [Va]⁴, Sar⁷] AVP (dVSAVP), rendered the NDI-affected dogs near normal in terms of water intake and urine osmolality.