Abstract
Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.
Highlights
Tight regulation of water homeostasis is essential for most physiological processes in all living organisms
The aquaporin 2 (AQP2)-collecting duct (CD)-KO mice survived to adulthood, despite a severe urinary concentration defect [97]. These findings suggest that AQP2 expressed in the connecting tubule (CNT) is fundamental to the rescue of the lethal phenotype observed in total AQP2 knockout mice and that it cannot be compensated for by other mechanisms
We provided compelling evidence that SCT induces a dose-dependent rise in intracellular cyclic adenosine monophosphate (cAMP) concentrations in CD tubule suspensions and promotes AQP2 apical expression in freshly isolated kidney slices from control and AVPR2-KO mice
Summary
Tight regulation of water homeostasis is essential for most physiological processes in all living organisms. The remaining 18 to 20 L of the forming urine reaching the distal tubules and the collecting ducts are subjected to regulated water reabsorption depending upon plasma osmolality and blood volume, defining the final urine volume to be excreted (1.5 to 2 L/24 h). The exit pathway for water entering the cells is represented by aquaporin 3 and 4 (AQP3/4), expressed at the basolateral membrane of the same cells mediating water flux to the extracellular fluid and to the blood. This process restores plasma osmolality and volume and is regulated by a negative feedback. We will focus our attention on the genetic defects leading to congenital NDI
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