Mini-Review Article

The (Pro)renin Receptor - A Regulatory Nodal Point in Disease Networks

Author(s): Heiko Funke-Kaiser* and Thomas Unger

Volume 24, Issue 14, 2023

Published on: 25 October, 2023

Page: [1093 - 1098] Pages: 6

DOI: 10.2174/0113894501250617231016052930

Price: $65

Abstract

Experimental inhibition of the (pro)renin receptor [(P)RR] is a promising therapeutic strategy in different disease models ranging from cardiorenal to oncological entities. Here, we briefly review the direct protein-protein interaction partners of the (P)RR and the plethora of distinct diseases in which the (P)RR is involved.

The first structural work on the (P)RR using AlphaFold, which was recently published by Ebihara et al., is the center of this mini-review since it can mechanistically link the protein-protein interaction level with the pathophysiological level.

More detailed insights into the 3D structure of the (P)RR and its interaction domains might guide drug discovery on this novel target. Finally, antibody- and small molecule-based approaches to inhibit the (P)RR are shortly discussed.

Keywords: (Pro)renin receptor (P)RR, protein-protein interaction partners, AlphaFold, drug target, oncology, cardiorenal.

Graphical Abstract
[1]
Rahman A, Matsuyama M, Ebihara A, et al. Antiproliferative effects of monoclonal antibodies against (Pro)renin receptor in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2020; 19(9): 1844-55.
[http://dx.doi.org/10.1158/1535-7163.MCT-19-0228] [PMID: 32669314]
[2]
Yamamoto H, Kaneko K, Ohba K, et al. Increased expression of (pro)renin receptor in aldosterone-producing adenomas. Peptides 2013; 49: 68-73.
[http://dx.doi.org/10.1016/j.peptides.2013.08.022] [PMID: 24025599]
[3]
Pareja F, Brandes AH, Basili T, et al. Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. Nat Commun 2018; 9(1): 3533.
[http://dx.doi.org/10.1038/s41467-018-05886-y] [PMID: 30166553]
[4]
Humphries H, Brasch HD, van Schaijik B, Tan ST, Itinteang T. Expression of components of the renin-angiotensin system by the embryonic stem cell–like population within keloid lesions. Plast Reconstr Surg 2019; 144(2): 372-84.
[http://dx.doi.org/10.1097/PRS.0000000000005867] [PMID: 31348346]
[5]
Shivapathasundram G, Wickremesekera AC, Brasch HD, et al. Expression of components of the renin-angiotensin system by the putative stem cell population within WHO Grade I meningioma. Front Surg 2019; 6: 23.
[http://dx.doi.org/10.3389/fsurg.2019.00023] [PMID: 31157231]
[6]
van Schaijik B, Tan ST, Marsh RW, Itinteang T. Expression of (pro)renin receptor and its effect on endothelial cell proliferation in infantile hemangioma. Pediatr Res 2019; 86(2): 202-7.
[http://dx.doi.org/10.1038/s41390-019-0430-8] [PMID: 31091531]
[7]
Solano-Iturri JD, Echevarría E, Unda M, et al. Clinical implications of (Pro)renin receptor (PRR) expression in renal tumours. Diagnostics 2021; 11(2): 272.
[http://dx.doi.org/10.3390/diagnostics11020272] [PMID: 33578778]
[8]
Larrinaga G, Calvete-Candenas J, Solano-Iturri JD, et al. (Pro)renin receptor is a novel independent prognostic marker in invasive urothelial carcinoma of the bladder. Cancers 2021; 13(22): 5642.
[http://dx.doi.org/10.3390/cancers13225642] [PMID: 34830803]
[9]
Lian H, Wang X, Wang J, et al. Heart-specific overexpression of (pro)renin receptor induces atrial fibrillation in mice. Int J Cardiol 2015; 184: 28-35.
[http://dx.doi.org/10.1016/j.ijcard.2015.01.088] [PMID: 25697868]
[10]
Ono M, Sakao Y, Tsuji T, et al. Role of intrarenal (pro)renin receptor in ischemic acute kidney injury in rats. Clin Exp Nephrol 2015; 19(2): 185-96.
[http://dx.doi.org/10.1007/s10157-014-0979-9] [PMID: 24817138]
[11]
Ludwig J, Kerscher S, Brandt U, et al. Identification and characterization of a novel 9.2-kDa membrane sector-associated protein of vacuolar proton-ATPase from chromaffin granules. J Biol Chem 1998; 273(18): 10939-47.
[http://dx.doi.org/10.1074/jbc.273.18.10939] [PMID: 9556572]
[12]
Funke-Kaiser H, Zollmann FS, Schefe JH, Unger T. Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage. Hypertens Res 2010; 33(2): 98-104.
[http://dx.doi.org/10.1038/hr.2009.206] [PMID: 20010781]
[13]
Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109(11): 1417-27.
[http://dx.doi.org/10.1172/JCI0214276] [PMID: 12045255]
[14]
Nguyen G, Burcklé CA, Sraer JD. Renin/prorenin-receptor biochemistry and functional significance. Curr Hypertens Rep 2004; 6(2): 129-32.
[http://dx.doi.org/10.1007/s11906-004-0088-3] [PMID: 15010017]
[15]
Schefe JH, Menk M, Reinemund J, et al. A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res 2006; 99(12): 1355-66.
[http://dx.doi.org/10.1161/01.RES.0000251700.00994.0d] [PMID: 17082479]
[16]
Cruciat CM, Ohkawara B, Acebron SP, et al. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 2010; 327(5964): 459-63.
[http://dx.doi.org/10.1126/science.1179802] [PMID: 20093472]
[17]
Hermle T, Guida MC, Beck S, Helmstädter S, Simons M. Drosophila ATP6AP2/VhaPRR functions both as a novel planar cell polarity core protein and a regulator of endosomal trafficking. EMBO J 2013; 32(2): 245-59.
[http://dx.doi.org/10.1038/emboj.2012.323] [PMID: 23292348]
[18]
Abbas YM, Wu D, Bueler SA, Robinson CV, Rubinstein JL. Structure of V-ATPase from the mammalian brain. Science 2020; 367(6483): 1240-6.
[http://dx.doi.org/10.1126/science.aaz2924] [PMID: 32165585]
[19]
Kanda A, Noda K, Ishida S. ATP6AP2/(pro)renin receptor contributes to glucose metabolism via stabilizing the pyruvate dehydrogenase E1 β subunit. J Biol Chem 2015; 290(15): 9690-700.
[http://dx.doi.org/10.1074/jbc.M114.626713] [PMID: 25720494]
[20]
Peters J. The (pro)renin receptor and its interaction partners. Pflugers Arch 2017; 469(10): 1245-56.
[http://dx.doi.org/10.1007/s00424-017-2005-z] [PMID: 28620832]
[21]
Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021; 596(7873): 583-9.
[http://dx.doi.org/10.1038/s41586-021-03819-2] [PMID: 34265844]
[23]
Fontana P, Dong Y, Pi X, et al. Structure of cytoplasmic ring of nuclear pore complex by integrative cryo-EM and AlphaFold. Science 2022; 376(6598): eabm9326.
[http://dx.doi.org/10.1126/science.abm9326] [PMID: 35679401]
[24]
Callaway E. Scientists are using AI to dream up revolutionary new proteins. Nature 2022; 609(7928): 661-2.
[http://dx.doi.org/10.1038/d41586-022-02947-7] [PMID: 36109683]
[25]
Ebihara A, Sugihara D, Matsuyama M, et al. Mapping the protein binding site of the (pro)renin receptor using in silico 3D structural analysis. Hypertens Res 2023; 46(4): 959-71.
[http://dx.doi.org/10.1038/s41440-022-01094-w] [PMID: 36481966]
[26]
Wang R, Long T, Hassan A, et al. Cryo-EM structures of intact V-ATPase from bovine brain. Nat Commun 2020; 11(1): 3921.
[http://dx.doi.org/10.1038/s41467-020-17762-9] [PMID: 32764564]
[27]
Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: From flies to human disease. J Invest Dermatol 2009; 129(7): 1614-27.
[http://dx.doi.org/10.1038/jid.2008.445] [PMID: 19177135]
[28]
Garber K. Drugging the Wnt pathway: Problems and progress. J Natl Cancer Inst 2009; 101(8): 548-50.
[http://dx.doi.org/10.1093/jnci/djp084] [PMID: 19351922]
[29]
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487(7407): 330-7.
[http://dx.doi.org/10.1038/nature11252] [PMID: 22810696]
[30]
Huang Y, Wongamorntham S, Kasting J, et al. Renin increases mesangial cell transforming growth factor-β1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 2006; 69(1): 105-13.
[http://dx.doi.org/10.1038/sj.ki.5000011] [PMID: 16374430]
[31]
Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: Oncogene and non-oncogene addiction. Cell 2009; 136(5): 823-37.
[http://dx.doi.org/10.1016/j.cell.2009.02.024] [PMID: 19269363]
[32]
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029-33.
[http://dx.doi.org/10.1126/science.1160809] [PMID: 19460998]
[33]
Riediger F, Quack I, Qadri F, et al. Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol 2011; 22(12): 2193-202.
[http://dx.doi.org/10.1681/ASN.2011020200] [PMID: 22034640]
[34]
Wang C, Hu Q, Shen HM. Pharmacological inhibitors of autophagy as novel cancer therapeutic agents. Pharmacol Res 2016; 105: 164-75.
[http://dx.doi.org/10.1016/j.phrs.2016.01.028] [PMID: 26826398]
[35]
Matavelli LC, Huang J, Siragy HM. (Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. Clin Exp Pharmacol Physiol 2010; 37(3): 277-82.
[http://dx.doi.org/10.1111/j.1440-1681.2009.05292.x] [PMID: 19769609]
[36]
Eckhardt BL, Francis PA, Parker BS, Anderson RL. Strategies for the discovery and development of therapies for metastatic breast cancer. Nat Rev Drug Discov 2012; 11(6): 479-97.
[http://dx.doi.org/10.1038/nrd2372] [PMID: 22653217]
[37]
Banani SF, Lee HO, Hyman AA, Rosen MK. Biomolecular condensates: Organizers of cellular biochemistry. Nat Rev Mol Cell Biol 2017; 18(5): 285-98.
[http://dx.doi.org/10.1038/nrm.2017.7] [PMID: 28225081]
[40]
Available from: https://dewpointx.com/
[41]
Nielsch U, Schäfer S, Wild H, Busch A. One target–multiple indications: A call for an integrated common mechanisms strategy. Drug Discov Today 2007; 12(23-24): 1025-31.
[http://dx.doi.org/10.1016/j.drudis.2007.10.004] [PMID: 18061881]
[42]
Hoshijima M, Chien KR. Mixed signals in heart failure: Cancer rules. J Clin Invest 2002; 109(7): 849-55.
[http://dx.doi.org/10.1172/JCI0215380] [PMID: 11927610]
[43]
Baruah VJ, Paul R, Gogoi D, et al. Integrated computational approach toward discovery of multi-targeted natural products from Thumbai ( Leucas aspera ) for attuning NKT cells. J Biomol Struct Dyn 2022; 40(7): 2893-907.
[http://dx.doi.org/10.1080/07391102.2020.1844056] [PMID: 33179569]
[44]
Mohammad AH, Kim SH, Bertos N, et al. Elevated V-ATPase activity following PTEN loss Is required for enhanced oncogenic signaling in breast cancer. Mol Cancer Res 2020; 18(10): 1477-90.
[http://dx.doi.org/10.1158/1541-7786.MCR-20-0088] [PMID: 32587106]
[45]
Morosin SK, Delforce SJ, Kahl RGS, Corbisier de Meaultsart C, Lumbers ER, Pringle KG. The (pro)renin receptor and soluble (pro)renin receptor in choriocarcinoma. Reproduction 2021; 162(5): 375-84.
[http://dx.doi.org/10.1530/REP-20-0650] [PMID: 34423782]
[46]
Wang J, Shibayama Y, Zhang A, et al. (Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations. Br J Cancer 2019; 120(2): 229-37.
[http://dx.doi.org/10.1038/s41416-018-0350-0] [PMID: 30555158]
[47]
Martin JH, Mohammed R, Delforce SJ, et al. Role of the prorenin receptor in endometrial cancer cell growth. Oncotarget 2022; 13(1): 587-99.
[http://dx.doi.org/10.18632/oncotarget.28224] [PMID: 35401936]
[48]
Kouchi M, Shibayama Y, Ogawa D, Miyake K, Nishiyama A, Tamiya T. (Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway. J Neurosurg 2017; 127(4): 819-28.
[http://dx.doi.org/10.3171/2016.9.JNS16431] [PMID: 28059652]
[49]
Ohba K, Endo M, Sato S, Kashio-Yokota Y, Hirose T, Takahashi K. (Pro)renin receptor/ATP6AP2 is required for autophagy and regulates proliferation in lung adenocarcinoma cells. Genes Cells 2020; 25(12): 782-95.
[http://dx.doi.org/10.1111/gtc.12812] [PMID: 33020972]
[50]
Shibayama Y, Fujimori T, Nguyen G, et al. (Pro)renin receptor is crucial for Wnt/β-catenin-dependent genesis of pancreatic ductal adenocarcinoma. Sci Rep 2015; 5(1): 8854.
[http://dx.doi.org/10.1038/srep08854] [PMID: 25747895]
[51]
Patel NR, K C R, Blanks A, Li Y, Prieto MC, Meadows SM. Endothelial cell polarity and extracellular matrix composition require functional ATP6AP2 during developmental and pathological angiogenesis. JCI Insight 2022; 7(19): e154379.
[http://dx.doi.org/10.1172/jci.insight.154379] [PMID: 35998033]
[52]
Tani Y, Yamada S, Inoshita N, Hirata Y, Shichiri M. Regulation of growth hormone secretion by (pro)renin receptor. Sci Rep 2015; 5(1): 10878.
[http://dx.doi.org/10.1038/srep10878] [PMID: 26039928]
[53]
Mohammad AH, Assadian S, Couture F, et al. V-ATPase-associated prorenin receptor is upregulated in prostate cancer after PTEN loss. Oncotarget 2019; 10(48): 4923-36.
[http://dx.doi.org/10.18632/oncotarget.27075] [PMID: 31452834]
[54]
Ma H, Dong XF, Cao XR, et al. Pro-renin receptor overexpression promotes Angiotensin II–Induced abdominal aortic aneurysm formation in apolipoprotein E-Knockout mice. Hum Gene Ther 2020; 31(11-12): 639-50.
[http://dx.doi.org/10.1089/hum.2019.124] [PMID: 31992084]
[55]
Quadri SS, Culver S, Siragy HM. Prorenin receptor mediates inflammation in renal ischemia. Clin Exp Pharmacol Physiol 2018; 45(2): 133-9.
[http://dx.doi.org/10.1111/1440-1681.12868] [PMID: 28980339]
[56]
Fang H, Deng M, Zhang L, et al. Role of (pro)renin receptor in albumin overload-induced nephropathy in rats. Am J Physiol Renal Physiol 2018; 315(6): F1759-68.
[http://dx.doi.org/10.1152/ajprenal.00071.2018] [PMID: 29846109]
[57]
Xiong J, Cao X, Qiao S, et al. (Pro)renin receptor is involved in myocardial damage in alcoholic cardiomyopathy. Alcohol Clin Exp Res 2019; 43(11): 2344-53.
[http://dx.doi.org/10.1111/acer.14188] [PMID: 31498445]
[58]
Ichihara A, Kaneshiro Y, Takemitsu T, et al. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006; 47(5): 894-900.
[http://dx.doi.org/10.1161/01.HYP.0000215838.48170.0b] [PMID: 16585419]
[59]
Susic D, Zhou X, Frohlich ED, Lippton H, Knight M. Cardiovascular effects of prorenin blockade in genetically spontaneously hypertensive rats on normal and high-salt diet. Am J Physiol Heart Circ Physiol 2008; 295(3): H1117-21.
[http://dx.doi.org/10.1152/ajpheart.00055.2008] [PMID: 18621861]
[60]
Zhang J, Cheng YJ, Luo CJ, Yu J. Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling. Front Pharmacol 2022; 13: 940365.
[http://dx.doi.org/10.3389/fphar.2022.940365] [PMID: 36034809]
[61]
Hu J, Tan Y, Chen Y, et al. Role of (pro)renin receptor in cyclosporin A-induced nephropathy. Am J Physiol Renal Physiol 2022; 322(4): F437-48.
[http://dx.doi.org/10.1152/ajprenal.00332.2021] [PMID: 35073210]
[62]
Dong X, Yu S, Wang Y, et al. (Pro)renin receptor-mediated myocardial injury, apoptosis, and inflammatory response in rats with diabetic cardiomyopathy. J Biol Chem 2019; 294(20): 8218-26.
[http://dx.doi.org/10.1074/jbc.RA119.007648] [PMID: 30952701]
[63]
Ichihara A, Hayashi M, Kaneshiro Y, et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J Clin Invest 2004; 114(8): 1128-35.
[http://dx.doi.org/10.1172/JCI21398] [PMID: 15489960]
[64]
Satofuka S, Ichihara A, Nagai N, et al. (Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation. Diabetes 2009; 58(7): 1625-33.
[http://dx.doi.org/10.2337/db08-0254] [PMID: 19389828]
[65]
Kaneshiro Y, Ichihara A, Sakoda M, et al. Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. J Am Soc Nephrol 2007; 18(6): 1789-95.
[http://dx.doi.org/10.1681/ASN.2006091062] [PMID: 17494887]
[66]
Li Z, Zhou L, Wang Y, et al. (Pro)renin receptor is an amplifier of Wnt/β-catenin signaling in kidney injury and fibrosis. J Am Soc Nephrol 2017; 28(8): 2393-408.
[http://dx.doi.org/10.1681/ASN.2016070811] [PMID: 28270411]
[67]
Ellmers LJ, Rademaker MT, Charles CJ, Yandle TG, Richards AM. (Pro)renin receptor blockade ameliorates cardiac injury and remodeling and improves function after myocardial infarction. J Card Fail 2016; 22(1): 64-72.
[http://dx.doi.org/10.1016/j.cardfail.2015.08.341] [PMID: 26362519]
[68]
Yoshida A, Kanamori H, Naruse G, et al. (Pro)renin Receptor Blockade Ameliorates Heart Failure Caused by Chronic Kidney Disease. J Card Fail 2019; 25(4): 286-300.
[http://dx.doi.org/10.1016/j.cardfail.2019.02.009] [PMID: 30769036]
[69]
Wang Y, Wang Y, Xue K, et al. (Pro)renin receptor antagonist PRO20 attenuates nephrectomy-induced nephropathy in rats via inhibition of intrarenal RAS and Wnt/β-catenin signaling. Physiol Rep 2021; 9(11): e14881.
[http://dx.doi.org/10.14814/phy2.14881] [PMID: 34057312]
[70]
Liu Y, Zuo S, Li X, et al. Interaction between V-ATPase B2 and (pro)renin receptors in promoting the progression of renal tubulointerstitial fibrosis. Sci Rep 2016; 6(1): 25035.
[http://dx.doi.org/10.1038/srep25035] [PMID: 27121029]
[71]
Ishii K, Takeuchi H, Fukunaga K, et al. Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade. Exp Lung Res 2015; 41(4): 199-207.
[http://dx.doi.org/10.3109/01902148.2014.993444] [PMID: 25844689]
[72]
Hirano Y, Takeuchi H, Suda K, et al. (Pro)renin receptor blocker improves survival of rats with sepsis. J Surg Res 2014; 186(1): 269-77.
[http://dx.doi.org/10.1016/j.jss.2013.08.004] [PMID: 24011922]
[73]
Hsieh YC, Wu PS, Lin YT, et al. (Pro)renin receptor inhibition attenuated liver steatosis, inflammation, and fibrosis in mice with steatohepatitis. FASEB J 2022; 36(10): e22526.
[http://dx.doi.org/10.1096/fj.202200594R] [PMID: 36063123]

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