The (Pro)renin Receptor in Kidney Development: Cellular, Molecular, and Signaling Mechanisms

The (pro)renin receptor ((P)RR), encoded by ATP6AP2, participates in kidney development and renal physiology through several potentially distinct activities: ligand-associated signaling, V-ATPase-related cellular functions, and generation of soluble (P)RR (s(P)RR). Experimental lineage-targeted ATP6AP2 perturbation supports requirements in ureteric bud branching and stromal–epithelial interactions, and a ureteric bud deletion model implicates Dot1/H3K79-associated changes. Nevertheless, deletion phenotypes do not by themselves establish that renin/prorenin binding causes the developmental defects. Wnt/V-ATPase interactions provide a mechanistic framework, whereas proposed links to GDNF/RET, Notch, PI3K/AKT, and metabolic pathways vary in evidentiary support and should not be interpreted as proven kidney-specific regulatory axes. Evidence for s(P)RR in sodium handling and adult renal injury must likewise be distinguished from its uncertain role in nephrogenesis. This review evaluates the strength and limitations of experimental findings, compares available developmental models, and outlines approaches to distinguish ligand-dependent actions from ATP6AP2/V-ATPase-associated functions. An association between abnormal nephrogenesis and later kidney disease is biologically plausible, but direct longitudinal evidence following developmental ATP6AP2 disruption remains limited.