Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus, which can be inherited or acquired, is char acterized by an inability to concentrate urine despite normal or elevated p lasma concentrations of the antidiuretic hormone arginine vasopressin. Poly uria, with hyposthenuria, and polydipsia are the cardinal clinical manifest ations of the disease. About 90% of patients with congenital nephrogenic di abetes insipidus are males with the X-linked recessive form of the disease (OMIM 304800) who have mutations in the arginine vasopressin receptor 2 gen e (AVPR2), which codes for the vasopressin V-2 receptor. The gene is locate d in chromosomal region Xq28. In <10% of the families studied, congenital n ephrogenic diabetes insipidus has an autosomal-recessive or autosomal-domin ant (OMIM 222000 and 125800, respectively) mode of inheritance. Mutations h ave been identified in the aquaporin-2 gene (AQP2), which is located in chr omosome region 12q13 and codes for the vasopressin-sensitive water channel. When studied in vitro, most AVPR2 mutations result in receptors that are t rapped intracellularly and are unable to reach the plasma membrane. A few m utant receptors reach the cell surface but are unable to bind arginine vaso pressin or to properly trigger an intracellular cyclic AMP signal. Similarl y, aquaporin-2 mutant proteins are misrouted and cannot be expressed at the luminal membrane. Chemical or pharmacological chaperones have been found t o reverse the intracellular retention of aquaporin-2 and arginine vasopress in receptor 2 mutant proteins. Because many hereditary diseases stem from t he intracellular retention of otherwise functional proteins, this mechanism may offer a new therapeutic approach to the treatment of those diseases th at result from errors in protein kinesis.