AVP-V2R · Function and regulation of the type 2 vasopressin receptor and 'V2R' in body fluid homeostasis

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Project objective

The hypophyseal hormone vasopressin regulates body water balance via the renal vasopressin-type 2 receptor (V2R). Several abnormalities of water balance, in states such as congestive heart failure, kidney, liver and brain disease, are caused by disturbance s in vasopressin action. The role of V2R regulation in these states is poorly understood. V2R is an important drug target with agonists such as dDVAP being used to manage central diabetes insipidus or treat children suffering from nightly urinary incontinence. Furthermore, the V2R is a candidate drug target for antagonists for the treatment of diseases associated with water retention. However, there is an almost complete lack of information of how this receptor is regulated at the protein level. Understanding of the basic regulation at the molecular level may lead to better treatment of several diseases with water balance disturbances.The purposes of the present studies are to use a targeted systems biology approach to:1) Determine the exact segmental and sub-cellular localization of the mouse, rat and human V2R.2) Analyse whether the V2R is regulated with respect to expression or sub-cellular trafficking under physiological conditions.3) Investigate whether V2R expression and sub-cellular trafficking is dys-regulated in pathophysiological conditions, and4) Develop a transgenic mouse with genetic deletion of the V2R in the kidney-collecting duct alone.This model of inherited nephrogenic diabetes insipidus will enable us to evaluate the extent to which the loss of a functional V2R affects the expression levels and function of other proteins that play key roles in water balance. At present, the understanding of multiple water balance disorders is incomplete. A molecular, cell biological and integrated physiological and pathophysiological understanding of V2R regulation will allow a better strategy for pharmaceutical exploitation of the V2R as a drug candidate for disease treatment.

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Participants

• UNIVERSITY OF AARHUS · AARHUS CCoordinatorDenmark

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