THE MOLECULAR-BASIS OF NEPHROGENIC DIABETES-INSIPIDUS

Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidney to the action of arginine-vasopressin (AVP); it may be due to genetic or acquired causes. Recent advances in molecular genetics have allowed the identification of the genes involved in congenital ND I. While inactivating mutations of the vasopressin V-2 receptor are re sponsible for X-linked NDI, autosomal recessive NDI is caused by inact ivating mutations of the vasopressin-regulated water channel aquaporin -2 (AQP-2). About 70 different mutations of the V-2 receptor have been reported, most of them missense mutations. The functionally character ized mutants show a loss of function due to defects in their synthesis , processing, intracellular transport, AVP binding, or interaction wit h the G protein/adenylyl cyclase system. Thirteen different mutations of the AQP-2 gene have been reported. Functional studies of three AQP- 2 mutations reveal impaired cellular routing as the main defect. The g reat number of different mutations with various functional defects hin ders the development of a specific therapy. Gene therapy may, however, eventually became applicable to the congenital forms of NDI. At prese nt all gene-therapeutic approaches lack safety and efficiency, which i s of particular relevance in a disease that is treatable by an adequat e water intake. The progress with regard to the molecular basis of ant idiuresis contributes to the understanding of acquired forms of NDI on a molecular level. Recent data show that lithium dramatically reduces the expression of AQP-2. Likewise, hypokalemia reduces the expression of this water channel. The exact mechanisms leading to this reduced e xpression of AQP-2 remain to be determined.