Renin dependent and independent functions of the (pro)renin receptor

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Binding of renin and prorenin to the (pro)renin receptor increases their enzymatic activity and up-regulates the expression of pro-fibrotic genes in vitro. These are the so called renin-dependent functions of the (pro)renin receptor. The renin-independent functions are related to its function as an accessory subunit of the V-ATPase and its participation in the signalosome. Since the V-ATPase is essential for cell survival, this complicates the analysis of the PRR in knockout experiments. To establish whether increased (pro)renin receptor expression could cause organ damage, we generated a transgenic mouse which conditionally overexpresses the mouse (pro)renin receptor. This transgenic mouse has no basal phenotype. With the present application we aim to examine whether overexpression of the receptor is pathogenic during activation of the renin angiotensin system or modulates disease severity in chronic kidney disease, diabetes mellitus or preeclampsia. A 28 kDa sized extracellular fragment can be cleaved from the 35 kDa sized full-length (pro)renin receptor. This soluble receptor fragment gets secreted and can be found in tissue and plasma. However, the pathophysiologic function of the soluble receptor is still unknown. To further examine the in vivo function of the soluble (pro)renin receptor, we are generating a transgenic mouse that overexpresses the soluble (pro)renin receptor. In vitro the soluble receptor is capable to rescue the knockout of the full-length receptor protein. By crossing the transgenic mouse overexpressing the soluble receptor with the (pro)renin receptor knockout mouse we will be able to examine whether the soluble receptor can also rescue the knockout of the full-length receptor in vivo. In addition, we will examine whether the soluble (pro)renin receptor can quench renin and prorenin in vivo and exerts protective effects on blood pressure and renal injury. This project will increase our knowledge about the (pro)renin receptor and its soluble part. The soluble (pro)renin receptor could represent a new target for therapeutic interventions in arterial hypertension and kidney disease.