Cellular targets for Ang IV: a molecular and pharmaceutical study

The renin-angiotensin system (RAS) is widely recognised as the most powerful signalling system for controlling sodium balance, body fluid volumes and arterial blood pressure. The major peptide of the RAS is the octapeptide angiotensin II, but there is accumulating evidence that this system encloses additional effector peptides such as Angiotensin IV (Ang IV). Ang IV has been suggested to exert its physiological effects by inhibiting the metabolism of other bioactive peptides (e.g. vasopressin, oxytocin) via the IRAP/ AT4 system. Yet, it is plausible that this system is capable of triggering intracellular events as well. The aim of this project is to perform a critical evaluation of this working hypothesis; more precisely, to explore the potential signalling mechanisms of the IRAP/AT4 system, to evaluate the physiological relevance of its activation and alteration of its enzymatic activity by Ang IV and to evaluate its possible involvement in pathophysiological processes. Finally, we will also evaluate the potential contribution of the IRAP/AT4 system in the biological effects of other angiotensin fragments, e.g. Ang-(1-7) and Ang III.