8.A.80 The Renin Receptor (RR) Family
The renin receptor functions as a renin and prorenin cellular receptor. It may mediate renin-dependent cellular responses by activating ERK1 and ERK2. By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, it may also play a role in the renin-angiotensin system (Nguyen et al. 2002).
(Pro)renin receptor (PRR) is highly expressed in the distal nephron. Administration of PRO20, a decoy peptide antagonist of PRR, to K+-loaded animals elevated plasma K+ levels and decreased urinary K+ excretion, accompanied by suppressed aldosterone excretion (Xu et al. 2016). High K+ downregulates Na+-Cl- cotransporter (NCC) expression but upregulated the renal outer medullary K+ channel (ROMK), calcium-activated potassium channel subunit alpha-1 (α-BK), α-Na+-K+-ATPase (α-NKA), and epithelial Na+ channel subunit beta (β-ENaC), all of which were blunted by PRO20. Following HK, urinary but not plasma renin was upregulated, which was blunted by PRO20. The same experiments performed using adrenalectomized (ADX) rats yielded similar results. Spironolactone treatment in high K+-loaded ADX rats attenuated kaliuresis but promoted natriuresis associated with the suppressed responses of β-ENaC, α-NKA, ROMK, and α-BK protein expression. Thus, renal PRR regulates K+ homeostasis through a local mechanism involving the intrarenal renin-angiotensin-aldosterone system and coordinates the regulation of several membrane Na+ and K+ transporting proteins (Xu et al. 2016).
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(Pro)renin receptor, PRR or ATP6AP2, ATP6IP2, CAPER, ELDF10, of 350 aas and 2 TMSs at the N- and C-termini. It plays a role in hypertensive disease (Danser 2015) and in planar cell polarity, including retinal laminar formation (Kanda 2015). ATP6AP2 is necessary for cell division, cell cycle progression and mitosis, and it inhibits ciliogenesis, thus promoting proliferation and preventing differentiation (Wanka et al. 2017). It is an assembly factor in the endoplasmic reticulum for the V-type ATPase (Guida et al. 2018). It forms a complex with ATP6AP1 (Q15904; 470 aas, two TMSs, N- and C-terminal), also called ATP6S1 and VATPS1. It has roles in various physiological processes, such as the cell cycle, autophagy, acid-base balance, energy metabolism, embryonic development, T cell homeostasis, water balance, blood pressure regulation, cardiac remodelling and maintenance of podocyte structure. These roles of the (P)RR are mediated by its effects on important biological systems and pathways including the tissue RAS, vacuolar H+-ATPase. It may contribute to the pathogenesis of diseases such as fibrosis, hypertension, pre-eclampsia, diabetic microangiopathy, acute kidney injury, cardiovascular disease, cancer and obesity (Ichihara and Yatabe 2019). PRR or ATP6AP2 is a type I transmembrane receptor that is capable of binding and activating prorenin and renin. Within the kidney, PRR is predominantly expressed in the distal nephron, particularly the intercalated cells, and activation of renal PRR contributes to renal injury in various rodent models of chronic kidney disease. Evidence has shwon that PRR is primarily cleaved by a site-1 protease to produce 28-kDa soluble PRR (sPRR) which seems to mediate most of the known pathophysiological functions of renal PRR through modulating the activity of the intrarenal renin-angiotensin system and provoking proinflammatory and profibrotic responses. Not only does sPRR activate renin, but it also directly binds and activates the angiotensin II type 1 receptor (Yang 2022). The protein binding site of the (pro)renin receptor using in silico 3D structural analysis has been mapped (Ebihara et al. 2023). (Pro)renin receptor blockade prevents increases in systolic blood pressure, sodium retention, and αENaC protein expression in the kidney of 2K1C goldblatt mice (Cárdenas et al. 2025). Downregulation of MPC1 promotes HCC cell proliferation and metastasis via the STAT3 pathway (Shan et al. 2025).
PRR of Homo sapiens
Vacuolar ATPase subunit (VHA-20), also called Pro)renin receptor, PRR, of 324 aas and 2 TMSs at the protein's N- and C-termini. VHA-20 is indispensable for normal larval development, acidification of the intestine, and nutrient uptake. Inhibition of vha-20 by RNAi leads to complex deterioration of water and pH gradients at the level of the whole organism including distention of the pseudocoelome cavity. The prorenin receptor thus appears to play roles in the regulation of body ion and water fluxes and in intestinal lumen acidification in nematodes (Zima et al. 2015).
VHA-20 (PRR) of Caenorhabditis elegans
Uncharacterized protein of 413 aas and 2 TMSs.
UP of Copidosoma floridanum
Vacuolar H+-ATPase M8.9 accessory subunitof 320 aas and 2 TMSs.
M8.9 subunit of Drosophila melanogaster
Uncharacterized protein of 342 aas and 3 TMSs, 2 N-terminal, and 1 C-terminal.
UP of Triticum urartu
Uncharacterized protein of 319 aas and 2 TMSs
UP of Manihot esculenta
Uncharacterized protein of 286 aas and 2 TMSs
UP of Volvox carteri f. nagariensis
Uncharacterized protein of 440 aas and 2 TMSs, N- and C-terminal.
UP of Ustilago hordei