Hereditary Nephrogenic Diabetes Insipidus: Molecular Basis of the Defect and Potential Novel Strategies for Treatment

Abstract

The antidiuretic hormone vasopressin regulates water reabsorption in the nephron by inducing apical plasma membrane exocytosis of the water channel aquaporin 2 in the kidney collecting duct principal cells. Disruption of this physiological mechanism by genetic alteration of either the vasopressin type 2 receptor gene or the aquaporin 2 gene, results in a rare genetic disorder known as nephrogenic diabetes insipidus, which main hallmark are polyuria and polydipsia. Over the last decades, analysis of patients affected by this disease helped genetists, clinicians, cell and molecular biologists and pharmacologists to better understand the physiology of water reabsorption in the kidney, the molecular basis of the disease and to propose protocols for rapid diagnosis and pharmacological handling of the disease. Much still remains to be done in terms of targeted therapy to make sure that these patients benefit from an improved quality of life. In this article we provide an overview on the most recent strategies under investigation for rescuing the mutated gene products activity or for bypassing defective vasopressin receptor signaling.