The interaction partners of (pro)renin receptor in the distal nephron

Abstract

The (pro)renin receptor (PRR), a key regulator of intrarenal renin-angiotensin system (RAS), is predominantly presented in podocytes, proximal tubules, distal convoluted tubules, and the apical membrane of collecting duct A-type intercalated cells, and plays a crucial role in hypertension, cardiovascular disease, kidney disease, and fluid homeostasis. In addition to its well-known renin-regulatory function, increasing evidence suggests PRR can also act in a variety of intracellular signaling cascades independently of RAS in the renal medulla, including Wnt/β-catenin signaling, cyclooxygenase-2 (COX-2)/prostaglandin E 2 (PGE 2) signaling, and the apelinergic system, and work as a component of the vacuolar H +-ATPase. PRR and these pathways regulate the expression/activity of each other that controlling blood pressure and renal functions. In this review, we highlight recent findings regarding the antagonistic interaction between PRR and ELABELA/apelin, the mutually stimulatory relationship between PRR and COX-2/PGE 2 or Wnt/β-catenin signaling in the renal medulla, and their involvement in the regulation of intrarenal RAS thereby control blood pressure, renal injury, and urine concentrating ability in health and patho-physiological conditions. We also highlight the latest progress in the involvement of PRR for the vacuolar H +-ATPase activity.

The emerging role of the apelinergic system in kidney physiology and disease

“…The kidney has a fundamental role in the renin-angiotensin system (RAS), which regulates blood pressure, salt retention, and fluid balance [32][33][34]. In the classical system, renin cleaves angiotensinogen to form angiotensin I (AngI), which is subsequently converted to AngII by angiotensin-I converting enzyme (ACE).…”

“…Intravenous (IV) apela-32 administration to salt-loaded salt-sensitive Dahl rats decreases medullary PRR and renin levels, urinary soluble PRR, renin, angiotensinogen and AngII excretion, blood pressure and kidney injury. It has been suggested that the apelinergic ligands antagonize renal PRR expression and RAS activation through cAMP-dependent but AR-independent signaling in the CD [34].…”

Cardiovascular aspects of the (pro)renin receptor: Function and significance

“…Given previous reports that megalin‐mediated endocytosis of renin and prorenin requires PRR, 4–6 Saigo et al have stated the close physiological relationship between PRR and renin/prorenin that intracellular alternative renin but not conventional renin/prorenin may be involved in PRR signaling 3 . This may challenge the idea that PRR is directly involved in multiple intracellular signaling cascades, including mitogen‐activated protein kinase (MAPK) signaling, wnt/β‐catenin signaling, cyclooxygenase‐2/prostaglandin E 2 signaling, and the apelinergic system 2,7 . Additionally, PRR also works as an accessory subunit of the vacuolar H + ‐ATPase (V‐ATPase) that regulates acid‐base homeostasis, cell survival, and urine acidification 7 …”

“…This may challenge the idea that PRR is directly involved in multiple intracellular signaling cascades, including mitogen‐activated protein kinase (MAPK) signaling, wnt/β‐catenin signaling, cyclooxygenase‐2/prostaglandin E 2 signaling, and the apelinergic system 2,7 . Additionally, PRR also works as an accessory subunit of the vacuolar H + ‐ATPase (V‐ATPase) that regulates acid‐base homeostasis, cell survival, and urine acidification 7 …”

“…3 This may challenge the idea that PRR is directly involved in multiple intracellular signaling cascades, including mitogen-activated protein kinase (MAPK) signaling, wnt/β-catenin signaling, cyclooxygenase-2/ prostaglandin E 2 signaling, and the apelinergic system. 2,7 Additionally, PRR also works as an accessory subunit of the vacuolar H + -ATPase (V-ATPase) that regulates acidbase homeostasis, cell survival, and urine acidification. 7 Although several previous studies have indicated that PRR is mainly present on the membrane within several tissues as assessed by immunofluorescence, [8][9][10] a recent study by Morimoto et al has reported that PRR protein was expressed in the cytoplasm and membrane in almost all organs as assessed by immunohistochemistry.…”