Angiotensin AT2 receptor function and drug discovery

The renin-angiotensin system (RAS) is one of the most important hormonal systems regulating both acute and chronic blood pressure. The main effector peptide of the RAS, known as angiotensin II, not only influences blood pressure but also exerts pro-inflammatory and pro-fibrotic effects on organs such as the heart, kidneys and vasculature. These effects are mediated by angiotensin II activating AT1 receptors. The AT2 receptor is the other main receptor subtype and the activation of this subtype counter-regulates AT1 receptor function. Drugs that inhibit AT1 receptor function directly (ARBs) or indirectly (ACE inhibitors) have been the cornerstone for controlling hypertension and hypertension-related end organ damage, although these drugs alone are usually not enough to regress pathological changes in the cardiovascular system that have developed over decades. To this end, we are developing novel drugs targeting AT2 receptors that are likely to exert inhibitory effects of the cardiovascular system. This overarching project investigates AT2 receptor pharmacology and pathophysiology from a number of perspectives including: - understanding AT2 receptor function in preclinical animal models of cardiovascular disease; - synthesising and developing novel compounds that activate AT2 receptors; - elucidating signalling mechanisms; - developing appropriate bioassays to facilitate drug discovery. This project engages with a cross-disciplinary team of researchers including pharmacologists, chemists, peptide chemists, biochemists and physiologists. Experiments range from molecular/cellular through to in vivo animal models of cardiovascular disease.