Pharmacological chaperones in nephrogenic diabetes insipidus: possibilities for clinical application.

The antidiuretic hormone arginine-vasopressin regulates water homeostasis in the human body by binding to its vasopressin type 2 receptor (V2R). Mutations in AVPR2, the gene encoding V2R, lead to the X-linked congenital form of nephrogenic diabetes insipidus (NDI), a disease characterized by the inability to concentrate urine in response to vasopressin; often this involves missense mutations or deletion of one or a few amino acids. In vitro V2R expression studies revealed that the function of most of these receptors is not disturbed, but due to their misfolding, the quality control mechanism of the endoplasmic reticulum (ER) retains these receptors inside the cell, thereby preventing their functioning at the plasma membrane. This review summarizes our current knowledge on ER retention of V2R mutants, and describes the different approaches that have been undertaken to restore the plasma membrane expression and function of V2R mutants in NDI in vitro and in vivo. The use of cell permeable receptor ligands (called 'pharmacological chaperones') appears promising for the treatment of NDI in a subset of patients.