In this issue of the Journal of the American Society of Nephrology (JASN), Wang et al. 1 unravel an intriguing new signaling cascade that involves the prorenin receptor (PRR) in the kidney collecting ducts (CDs) as a necessary component of the physiologic ability of the kidneys to concentrate urine. The pathway includes serial coupling between the vasopressin (AVP) V 2 receptor, the prostaglandin E 2 (PGE 2 ) EP 4 receptor, and PRR, all associated with CDs. Many factors are known to modulate urine concentration-both hormones, like angiotensin II, aldosterone, cortisol, and endothelin and paracrine factors, like ATP-whereas few are true mediators. It is fascinating to uncover what seems to be a new and nonredundant mediator pathway downstream from the AVP V 2 receptor. Here, at the intrarenal level, the findings indicate hierarchical interpositions of local PGE 2 EP 4 receptor-driven renin/prorenin-PRR interaction as necessary sequential mediators for the AVP V 2 effect on CD transepithelial water transport.The PRR was cloned in 2002 by Nguyen et al. 2 In its native form, it is a 35-kD protein that undergoes intracellular proteolysis. This gives rise to a full-length membrane integral form and a soluble PRR. The soluble form is cleaved by intracellular proprotein convertase/serine endoprotease furin and released into plasma and urine with the ability to bind renin and activate prorenin. 3 Finally, a truncated form is associated with the vacuolar H 1 -ATPase, 4 with activity that is enhanced by prorenin. 5 PRR ligands comprise prorenin and active renin, with proteolytic activities that are enhanced by binding. 2 In the kidney, PRR is predominantly associated with the CDs and the distal nephron. 6 The PRR is most abundant in microvilli at the apical surface of A-type intercalated cells. 6 Several groups have, in parallel studies, contributed converging observations on renal PRR and thus, bits to the puzzle. A prequel paper was published in October of 2015 showing the effect of nephron-specific deletion of PRR. 7 The phenotype was nephrogenic diabetes insipidus with lower levels of the apical water transport protein AQP2 in kidney tissue and impaired AVP V 2 receptor-induced cAMP formation in medulla tissue. 7 Impaired vasopressin signaling with attenuated cAMP formation had already been shown in vitro after siRNA depletion of PRR in MDCK cells. 5 On the basis of this, PRR seemed to be necessary for AVP signaling in principal cells of CDs and thus, baseline urine concentration. Previous data supported the observation indirectly, because Cp2l1 tra/tra (Grainyhead transcription factor) mice, which lacked type A-intercalated cells (that express PRR) in CDs, displayed mild polyuria. 8 What were the mechanisms by which PRR promoted cAMP signaling and the link to normal physiology? A physiologic role for PGs in the regulation of PRR was indicated by the observation that stimulation of medullary PRR and renin by angiotensin II depended on a PGE 2 EP 4 receptor. 9 An unequivocal function for the PGE 2 EP 4 receptor in renal ...