The (pro)renin receptor and cardiovascular disease

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The (pro)renin receptor (PRR) was initially believed to be a contributor to the pathogenesis of cardiovascular diseases via its involvement in the renin-angiotensin system (RAS). However, a recent paradigm shift suggests a new role for PRR, separate from the RAS, in contributing to cellular homeostasis. Specifically, PRR is thought to be essential for vacuolar H+-ATPase (V-ATPase) activity, and to act as an adaptor between the V-ATPase and the Wnt signalling pathway. Recent PRR conditional knockout studies have confirmed the link between V-ATPase and PRR, with deletion resulting in the accumulation of autophagic vacuoles and animal lethality. Additionally, cleavage by furin at a single site within full-length PRR results in the production of a soluble form of the receptor (sPRR), which is detectable in plasma. Soluble PRR is hypothesised to bind to specific ligands and receptors and mediate signal transduction pathways. The mechanism by which full-length PRR contributes to V-ATPase activity and signal transduction, and the role of sPRR in signal transduction remains unclear. We will determine the molecular details by which PRR contributes to V-ATPase activity, signal transduction and membrane receptor trafficking with a combination of biochemical, cell biology and transgenic animal approaches. Overall, the information generated from this project will reveal the role of PRR in cellular biology and disease.