Potential therapeutic effect of beta3-adrenergic receptor agonists on X-linked Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is a kidney disorder characterized by the kidney's inability to concentrate urine in response to the antidiuretic hormone vasopressin. In NDI the proper amount of water cannot be reabsorbed. As a consequence a large amount of water is instead voided as dilute urine, leaving NDI patients chronically thirsty and in danger of dehydration. NDI patients require a steady supply of water to alleviate their thirst and prevent dehydration. The X-linked NDI (X-NDI) is the most common type of NDI and is caused by mutations of the AVPR2 gene that results in defective vasopressin receptor. The target of vasopressin is the water channel AQP2 that allows water reabsorption in the kidney. Since in this form of NDI the hormonal pathway is impaired, AQP2 is unable to perform its physiological role. None of the current therapeutic interventions are highly effective in this form of NDI and none of them are focused on AQP2 as the pharmacological target. We have evidence that beta-adrebergic receptors type 3 (BAR3) are expressed in the same renal cells expressing the vasopressin receptore. BAR3 stimulation with a selective agonist is able to recue AQP2 function in the absence of vasopressin action and dramatically reduce the urine volume in the mouse model of X-NDI. The aim of this project is to test whether BAR 3 agonists can be used as an alternative, highly effective, therapeutic approach in the management of of X-NDI.