LAUSR

A. Ichihara and M. S. Yatabe (The (pro)renin receptor in health and disease. Nat. Rev. Nephrol. 15, 693–712 (2019))1. The (pro)renin receptor (PRR; also known as ATP6AP2) was first discovered in 1998 in a biochemical purification approach that yielded a 8.9 kDa fragment of a membraneassociated protein. This fragment associated with the proton pump VATPase and was hence given the gene name ATP6AP2 (ref.2). However, in 2002, a seminal paper by Nguyen and colleagues3 suggested that the fragment belonged to a larger protein — the PRR — that can bind to prorenin, the precursor of renin, on the cell surface, thereby facilitating its processing to renin. The circulatory levels of renin are normally ten times lower than those of prorenin. Moreover, elevated prorenin levels correlate with the microvascular complications of diabetes and hypertension, suggesting that prorenin may contribute to the extrarenal effects of renin. The PRR therefore represented a promising drug target to prevent endorgan damage mediated by the renin– angiotensin system (RAS). As a result, the PRR attracted a lot of attention, which was aided to a large extent by its flashy name. Despite almost two decades of PRR research, it is still far from clear how prorenin is processed and, most importantly, whether this processing is physiologically relevant for the RAS. Unlike previous reviews of this research area4,5, the article by Ichihara and Yatabe1 and another recent review by N. Ramkumar and D. E. Kohan published in Kidney International6 do not acknowledge this uncertainty. A major issue plaguing the field is that deletion of the ATP6AP2 gene causes embryonic lethality. For this reason, most lossoffunction studies either use a blocking peptide against the handle region or conditional mouse knockouts. Whereas the efficiency of the peptide approach remains controversial7, the conditional knockout approach has so far mainly revealed VATPasedependent effects, as reflected by reduced Sorbonne Paris Cité, Hôpital NeckerEnfants Malades, Paris, France. 2Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 3MaxDelbrück Center for Molecular Medicine (MDC), BerlinBuch, Germany. 4University of Lübeck, Institute for Biology, Lübeck, Germany. 5CharitéUniversitätsmedizin Berlin, Berlin, Germany. 6German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany. 7Experimental and Clinical Research Center, a joint cooperation of MaxDelbrück Center for Molecular Medicine and CharitéUniversitätsmedizin Berlin, Berlin, Germany. ✉email: [email protected]