The (pro)renin receptor in health and disease

The (pro)renin receptor ((P)RR) was first identified as a single-transmembrane receptor in human kidneys and initially attracted attention owing to its potential role as a regulator of the tissue renin–angiotensin system (RAS). Subsequent studies found that the (P)RR is widely distributed in organs throughout the body, including the kidneys, heart, brain, eyes, placenta and the immune system, and has multifaceted functions in vivo. The (P)RR has roles in various physiological processes, such as the cell cycle, autophagy, acid–base balance, energy metabolism, embryonic development, T cell homeostasis, water balance, blood pressure regulation, cardiac remodelling and maintenance of podocyte structure. These roles of the (P)RR are mediated by its effects on important biological systems and pathways including the tissue RAS, vacuolar H + -ATPase, Wnt, partitioning defective homologue (Par) and tyrosine phosphorylation. In addition, the (P)RR has been reported to contribute to the pathogenesis of diseases such as fibrosis, hypertension, pre-eclampsia, diabetic microangiopathy, acute kidney injury, cardiovascular disease, cancer and obesity. Current evidence suggests that the (P)RR has key roles in the normal development and maintenance of vital organs and that dysfunction of the (P)RR is associated with diseases that are characterized by a disruption of the homeostasis of physiological functions. Here, the authors discuss the multiple functions of the (pro)renin receptor in physiological processes, including blood pressure regulation, energy metabolism and autophagy, as well as its roles in the pathogenesis of diseases including fibrosis, chronic kidney disease, pre-eclampsia and cancer. Key points The (pro)renin receptor ((P)RR) is a ubiquitously expressed, single-transmembrane receptor protein with a molecular mass of 39 kDa; the carboxy-terminal domain of the (P)RR binds to the vacuolar H + -ATPase (V-ATPase). Ligands that bind to the (P)RR amino-terminal domain include renin, prorenin, partitioning defective homologue 3 (Par3), PDH E1 β-subunit (PDHB), LDL receptor-related protein 6 (LRP6), phosphatase of regenerating liver 1 (PRL1), actin binding LIM protein 2 (abLIM2), capping actin protein of muscle Z-line subunit-α2 (CAPZA2) and vertebrate homologue of flamingo (CELSR). At least three enzymes — furin, ADAM19 and site 1 protease (S1P) — cleave off the amino-terminal domain of the (P)RR to produce soluble (P)RR. In addition to angiotensin II generation, t