Prorenin Receptor, a Necessary Component in Urine Concentration Mechanism.

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) V2 receptor, the prostaglandin E2 (PGE2) EP4 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 V2 receptor. Here, at the intrarenal level, the findings indicate hierarchical interpositions of local PGE2 EP4 receptor–driven renin/prorenin-PRR interaction as necessary sequential mediators for the AVP V2 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-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 ismost 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 V2 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 (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 PGE2 EP4 receptor.9 An unequivocal function for the PGE2 EP4 receptor in renal water handling was shown in 2015.10 The EP4 receptor couples to a Gs protein, leading to adenylate cyclase stimulation and formation of cAMP. In the kidney, the EP4 receptor is associated with CDs, glomeruli, and renal resistance vessels.11–13 Although first observations in mice with global EP4 receptor deletion showed amild diuresis only after low salt intake, no electrolyte disturbances, and impaired renin release from juxtaglomerular cells,14,15 the 2015 data indicated that EP4 receptors were physiologically stimulated by water deprivation in renal medulla.10Moreover, renal tubule– and CD–specific EP4 receptor deletion resulted in increased baseline diuresis, normal electrolyte excretion, impaired urine concentrating ability with attenuated AQP2 protein abundance, and impaired cAMP formation but intact circulating levels of AVP.10 Thus, similar to CD–specific PRR deletion, the CD EP4–deleted phenotype exhibited nephrogenic insipidus. This observation provided a mechanistic clue to the previous observations that, in experimental nephrogenic diabetes insipidus models in rats and mice, EP4 receptor agonists alleviated increased diuresis16,17 Similar to the PRR, EP4 receptor seems necessary for baseline renal water conservation and urine concentration ability through an intrarenal mechanism. This article byWang et al.1 takes off at this site with putative roles for CD EP4 receptor and PRR in urine concentration and shows their interaction by a series of complementary pharmacologic and genetic in vivo and in vitro intervention approaches. Water deprivation stimulated intercalated cell production of PRR, release of soluble PRR, and prorenin protein and mRNAabundance inmedulla tissue and renin in urine but not plasma. Both PRR and renin stimulation depended on the EP4 receptor.1 Intrarenal infusion of PRR antagonist attenuated Published online ahead of print. Publication date available at www.jasn.org.