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 [Val4, Sar7] AVP (dVSAVP), rendered the NDI-affected dogs near normal in terms of water intake and urine osmolality.
Luzius
H
H
Max-Planck-Institut für Biophysik, Frankfurt, FRG.
Jans
D A
DA
Grünbaum
E G
EG
Moritz
A
A
Rascher
W
W
Fahrenholz
F
F
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D001667:Binding, Competitive / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003919:Diabetes Insipidus / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D019204:GTP-Binding Proteins / Q000502:physiology; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D011945:Receptors, Angiotensin / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism*; D012969:Sodium Fluoride / Q000494:pharmacology
D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D005576:Colforsin; D006160:Guanosine Triphosphate; D012969:Sodium Fluoride; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases