A Low Affinity Vasopressin V2-Receptor in Inherited Nephrogenic Diabetes Insipidus
| Title: | A Low Affinity Vasopressin V2-Receptor in Inherited Nephrogenic Diabetes Insipidus |
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| Authors: | Luzius, Heike; Jans, David A.; Grunbaum, Ernst-Gunther; Moritz, Andreas; Rascher, MD, Wolfgang; Fahrenholz, Falk |
| Publisher: | Journal of Receptor Research |
| Date Published: | January 01, 1992 |
| Reference Number: | 311 |
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.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
The authors extracted from two of the NDI pups the kidney membranes containing all the molecular structures involved in initiating and conducting the water reabsorption process, including: the vasopressin-2 receptors, G-proteins, adenylyl cyclase system, cAMP, protein kinase-A and specific water transporting proteins. They prepared the membranes and incubated them with the antidiuretic hormone, arginine vasopressin (AVP), the hormone that initiates the water reabsorption and urine concentrating process. They did this in order to determine the approximate amount of V2Rs and the V2Rs' affinity for AVP. They compared the results to similarly prepared and incubated V2Rs from two dogs not affected with NDI. The authors found that the NDI pups had the normal amount of V2Rs, but that these V2Rs had a 10-fold lower binding affinity for AVP than normal V2Rs.
In contrast, both the experimental and control group kidney membranes showed equally normal stimulation of adenylyl cyclase. This implies normal adenylyl cyclase and G-protein function in the NDI huskies. This indicated that defective V2Rs were responsible for this dog family's NDI. This laboratory study was the platform for the next phase of research which used live animals: two NDI affected husky pups and two normal beagles.
The authors knew the NDI pups had normal numbers of V2Rs that were functional, but had a low binding affinity for AVP. They reasoned if they injected the pups with high concentrations of synthetic analogs of AVP (DDAVP and DVSAVP) there would be so much synthetic AVP available that even V2Rs with low binding affinity would bind in amounts sufficient to reverse NDI.
This proved true as the injected pups showed reduced urine output and more highly concentrated urine one hour after injection. The NDI pups also responded to administration of very high doses of DDAVP, for 9 days, and DVSAVP, for 6 days. They became almost identical to the non-treated controls in terms of water intake and concentrated urine.
This study of NDI dogs is consistent with studies with NDI humans in that it points to a defect of the V2R being involved in this form of NDI. It is inconsistent with the human studies in that NDI humans do not respond to DDAVP or DVSAVP with reduced urine output and water intake, or more highly concentrated urine.