The (pro)renin receptor and its interaction partners.

The prorenin receptor was originally discovered as a receptor that binds renin and prorenin, thereby inducing pro-fibrotic intracellular signal cascades. These effects are partially mediated in vitro by angiotensin (ANG) and partially independent of ANG. Consequently, inhibitors of the interaction between the prorenin and the (pro)renin receptor (PRR) were designed hoping that they may prevent fibrotic tissue damage, for instance, in the kidney. However, this concept was challenged by the fact that overexpression of the PRR was not harmful at all, whereas depletion of the PRR was lethal or markedly detrimental. Furthermore, the high levels of prorenin needed to activate the PRR may not be reached in vivo. As it turned out, the PRR instead exhibited a variety of important functions that has nothing to do with the name given to the protein. Thus, the PRR was identified as an accessory subunit of vesicular (v)-ATPases, representing an essential chaperon for the assembly of v-ATPase subunits. In this respect, the gene encoding the PRR was also named ATP6AP2. Finally, the PRR is an essential component of the canonical and non-canonical PCP Wnt pathways. Thus, the PRR is essential for lysosomal functions, such as endocytosis, secretion, and autophagy as well as for cell division and differentiation, embryonic development, organogenesis, and stem cell biology.