Molecular basis and clinical features of nephrogenic diabetes insipidus

Abstract

Maintenance of water and electrolyte homeostasis is central to mammalian survival and, therefore, under stringent hormonal control. Water homeostasis is achieved by balancing fluid intake with water excretion, governed by the antidiuretic action of arginine vasopressin. Arginine vasopressin stimulation of renal V2 vasopressin receptors in the basolateral membrane of principal cells induces aquaporin-2-mediated water reabsorption in the kidney. The importance of this system is apparent when mutations inactivate V2 vasopressin receptors and aquaporin-2 and cause the clinical phenotype of nephrogenic diabetes insipidus. To date, over 190 mutations in the V2 vasopressin receptors gene (AVPR2) and approximately 38 mutations in the aquaporin-2 gene have been identified in patients with inherited nephrogenic diabetes insipidus. Extensive in vitro expression and mutagenesis studies of V2 vasopressin receptors and aquaporin-2 have provided detailed insights into the molecular mechanisms of G-protein-coupled receptor and water channel dysfunction per se. Targeted deletions of AVPR2 and AQP2 in mice have extended the knowledge of nephrogenic diabetes insipidus pathophysiology and have stimulated testing of old and new ideas to therapeutically restore normal kidney function in animal models and patients with this disease. In this review, we summarize the current knowledge relevant to understand the molecular basis of inherited nephrogenic diabetes insipidus forms and the rationales for the current pharmacological treatment of patients with this illness.