A Low Affinity Vasopressin V₂-Receptor in Inherited Nephrogenic Diabetes Insipidus

Abstract

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 [Val4, Sar7] AVP (dVSAVP), rendered the NDI-affected dogs near normal in terms of water intake and urine osmolality.

Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

“…We presented several illustrative examples such as the presence of the SLiM DOC_MAPK_1 in the kangaroo rat AVPR2, which mediates docking with a kinase involved with cellular response to a diverse array of stimuli including osmotic stress (Pearson et al , 2001). This unique characteristic among placental mammals might have adaptive implications, since the importance of AVPR2 in the hypothalamic-renal regulation of water and electrolyte homeostasis became evident when mutations in the AVPR2 gene were associated with nephrogenic diabetes insipidus in humans, mice, dogs, and horses, a disease characterized by polyuria and polydipsia (Luzius et al , 1992; Böselt et al , 2009). …”

Successful Treatment of Partial Nephrogenic Diabetes insipidus with Thiazide and Desmopressin

“…DDAVP has been shown to be more effective in the patient with congenital diabetes insipidus with reduced renal blood flow and a partial vasopressin response. NDI-affected dogs have been shown to exhibit an antidiuretic response to very high doses of V2-specific agonists, consistent with their possessing V2 receptors of low affinity [12]. Inaba et al [7]reported that the binding capacity and maximum cAMP accumulation of R104C with COS-7 cells decreased by 10 and 50% of wild type, respectively.…”

Involvement of the V2 Vasopressin Receptor in Adaptation to Limited Water Supply

“…NDI is characterized by the inability to concentrate the urine and an increased urine volume. Inherited NDI is not only found in humans but also in mice, dogs and horses [14]–[16] indicating similar functional relevance of the V2R among mammals. However, there are several examples where patients managed NDI basically by appropriate water supply (family 4 in [17] and family 1 in [18]).…”