The (pro)renin receptor mediates constitutive PLZF-independent pro-proliferative effects which are inhibited by bafilomycin but not genistein

Kirsch,Sebastian; Schrezenmeier,Eva; Klare,Sabrina; Zaade,Daniela; Seidel,Kerstin; Schmitz,Jennifer; Bernhard,Sarah; Lauer,Dilyara; Slack,Mark; Goldin-Lang,Petra; Unger,Thomas; Zollmann,Frank S.; Funke-Kaiser,Heiko

doi:10.3892/ijmm.2014.1624

The (pro)renin receptor mediates constitutive PLZF-independent pro-proliferative effects which are inhibited by bafilomycin but not genistein

Authors:
- Sebastian Kirsch
- Eva Schrezenmeier
- Sabrina Klare
- Daniela Zaade
- Kerstin Seidel
- Jennifer Schmitz
- Sarah Bernhard
- Dilyara Lauer
- Mark Slack
- Petra Goldin-Lang
- Thomas Unger
- Frank S. Zollmann
- Heiko Funke-Kaiser
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Affiliations: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany, Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany, Evotec AG, Hamburg, Germany, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
Published online on: January 14, 2014 https://doi.org/10.3892/ijmm.2014.1624
Pages: 795-808
Copyright: © Kirsch et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The (pro)renin receptor [(P)RR] is crucial for cardio-renal pathophysiology. The distinct molecular mechanisms of this receptor are still incompletely understood. The (P)RR is able to interact with different signalling proteins such as promyelocytic leukemia zinc finger protein (PLZF) and Wnt receptors. Moreover, domains of the (P)RR are essential for V-ATPase activity. V-ATPase- and Wnt-mediated effects imply constitutive, i.e., (pro)renin-independent functions of the (P)RR. Regarding ligand-dependent (P)RR signalling, the role of prorenin glycosylation is currently unknown. Therefore, the aim of this study was to analyse the contribution of constitutive (P)RR activity to its cellular effects and the relevance of prorenin glycosylation on its ligand activity. We were able to demonstrate that high glucose induces (P)RR signal transduction whereas deglycosylation of prorenin abolishes its intrinsic activity in neuronal and epithelial cells. By using siRNA against (P)RR or PLZF as well as the PLZF translocation blocker genistein and the specific V-ATPase inhibitor bafilomycin, we were able to dissect three distinct sub-pathways downstream of the (P)RR. The V-ATPase function is ligand-independently associated with strong pro-proliferative effects whereas prorenin causes moderate proliferation in vitro. In contrast, PLZF per se [i.e., in the absence of (pro)renin] does not interfere with cell number.

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1	Funke-Kaiser H, Zollmann FS, Schefe JH and Unger T: Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage. Hypertens Res. 33:98–104. 2010. View Article : Google Scholar : PubMed/NCBI
2	Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T and Sraer JD: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 109:1417–1427. 2002. View Article : Google Scholar : PubMed/NCBI
3	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. 114:1128–1135. 2004.PubMed/NCBI
4	Ichihara A, Kaneshiro Y, Takemitsu T, et al: Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension. 47:894–900. 2006. View Article : Google Scholar : PubMed/NCBI
5	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. 18:1789–1795. 2007. View Article : Google Scholar : PubMed/NCBI
6	Susic D, Zhou X, Frohlich ED, Lippton H and Knight M: Cardiovascular effects of prorenin blockade in genetically spontaneously hypertensive rats on normal and high-salt diet. Am J Physiol Heart Circ Physiol. 295:H1117–H1121. 2008. View Article : Google Scholar : PubMed/NCBI
7	Ichihara A, Suzuki F, Nakagawa T, et al: Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol. 17:1950–1961. 2006. View Article : Google Scholar : PubMed/NCBI
8	Takahashi H, Ichihara A, Kaneshiro Y, et al: Regression of nephropathy developed in diabetes by (pro)renin receptor blockade. J Am Soc Nephrol. 18:2054–2061. 2007. View Article : Google Scholar : PubMed/NCBI
9	Muller DN, Klanke B, Feldt S, et al: (Pro)renin receptor peptide inhibitor ‘handle-region’ peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. Hypertension. 51:676–681. 2008.
10	Feldt S, Maschke U, Dechend R, Luft FC and Muller DN: The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling. J Am Soc Nephrol. 19:743–748. 2008. View Article : Google Scholar : PubMed/NCBI
11	Nguyen G and Muller DN: The biology of the (pro)renin receptor. J Am Soc Nephrol. 21:18–23. 2010. View Article : Google Scholar
12	Ryuzaki M, Ichihara A, Ohshima Y, et al: Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension. Hypertens Res. 34:301–307. 2011. View Article : Google Scholar : PubMed/NCBI
13	Kiyomoto H and Moriwaki K: Chronic blockade of the (pro)renin receptor ameliorates the kidney damage in the non-clipped kidney of Goldblatt hypertension. Hypertens Res. 34:289–291. 2011. View Article : Google Scholar : PubMed/NCBI
14	Nagai Y, Ichihara A, Nakano D, et al: Possible contribution of the non-proteolytic activation of prorenin to the development of insulin resistance in fructose-fed rats. Exp Physiol. 94:1016–1023. 2009. View Article : Google Scholar : PubMed/NCBI
15	Lavoi JL: Methods of treating or preventing obesity and obesity-related hypertension. Patentanmeldung WO 2009/143619 A1. 2009
16	Satofuka S, Ichihara A, Nagai N, et al: Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization. Invest Ophthalmol Vis Sci. 48:422–429. 2007. View Article : Google Scholar : PubMed/NCBI
17	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. 58:1625–1633. 2009. View Article : Google Scholar
18	Wilkinson-Berka JL, Heine R, Tan G, Tikellis C, Cooper ME, Nguyen G and Miller AG: The role of the (pro)renin receptor in developing ischaemic and diabetic retina. J Renin Angiotensin Aldosterone Syst. 9(Suppl 1): S82008.
19	Mahmud H, Sillje HH, Cannon MV, van Gilst WH and de Boer RA: Regulation of the (pro)renin-renin receptor in cardiac remodelling. J Cell Mol Med. 16:722–729. 2012. View Article : Google Scholar : PubMed/NCBI
20	Melnyk RA, Tam J, Boie Y, Kennedy BP and Percival MD: Renin and prorenin activate pathways implicated in organ damage in human mesangial cells independent of angiotensin II production. Am J Nephrol. 30:232–243. 2009. View Article : Google Scholar : PubMed/NCBI
21	Connelly KA, Advani A, Kim S, et al: The cardiac (pro)renin receptor is primarily expressed in myocyte transverse tubules and is increased in experimental diabetic cardiomyopathy. J Hypertens. 29:1175–1184. 2011. View Article : Google Scholar : PubMed/NCBI
22	Siragy HM and Huang J: Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp Physiol. 93:709–714. 2008. View Article : Google Scholar : PubMed/NCBI
23	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. 99:1355–1366. 2006. View Article : Google Scholar
24	Schefe JH, Neumann C, Goebel M, et al: Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren. J Hypertens. 26:1787–1794. 2008. View Article : Google Scholar : PubMed/NCBI
25	Katz SA, Opsahl JA, Abraham PA and Gardner MJ: The relationship between renin isoelectric forms and renin glycoforms. Am J Physiol. 267:R244–R252. 1994.PubMed/NCBI
26	Cruciat CM, Ohkawara B, Acebron SP, et al: Requirement of prorenin receptor and vacuolar H⁺-ATPase-mediated acidification for Wnt signaling. Science. 327:459–463. 2010. View Article : Google Scholar : PubMed/NCBI
27	Bader M: The second life of the (pro)renin receptor. J Renin Angiotensin Aldosterone Syst. 8:205–208. 2007. View Article : Google Scholar : PubMed/NCBI
28	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. 273:10939–10947. 1998. View Article : Google Scholar : PubMed/NCBI
29	Advani A, Kelly DJ, Cox AJ, et al: The (pro)renin receptor: site-specific and functional linkage to the vacuolar H⁺-ATPase in the kidney. Hypertension. 54:261–269. 2009. View Article : Google Scholar : PubMed/NCBI
30	Sihn G, Rousselle A, Vilianovitch L, Burckle C and Bader M: Physiology of the (pro)renin receptor: Wnt of change? Kidney Int. 78:246–256. 2010. View Article : Google Scholar : PubMed/NCBI
31	Cousin C, Bracquart D, Contrepas A, Corvol P, Muller L and Nguyen G: Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension. 53:1077–1082. 2009. View Article : Google Scholar : PubMed/NCBI
32	Yoshikawa A, Aizaki Y, Kusano K, et al: The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space. Hypertens Res. 34:599–605. 2011. View Article : Google Scholar : PubMed/NCBI
33	Senbonmatsu T, Saito T, Landon EJ, et al: A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy. EMBO J. 22:6471–6482. 2003. View Article : Google Scholar : PubMed/NCBI
34	Seifert R and Wenzel-Seifert K: Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol. 366:381–416. 2002. View Article : Google Scholar : PubMed/NCBI
35	Funke-Kaiser H, Reichenberger F, Köpke K, et al: Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation. Hum Mol Genet. 12:423–433. 2003. View Article : Google Scholar
36	Seidel K, Kirsch S, Lucht K, et al: The promyelocytic leukemia zinc finger (PLZF) protein exerts neuroprotective effects in neuronal cells and is dysregulated in experimental stroke. Brain Pathol. 21:31–43. 2011. View Article : Google Scholar : PubMed/NCBI
37	Jansen EJ and Martens GJ: Novel insights into V-ATPase functioning: distinct roles for its accessory subunits ATP6AP1/Ac45 and ATP6AP2/(pro)renin receptor. Curr Protein Pept Sci. 13:124–133. 2012. View Article : Google Scholar : PubMed/NCBI
38	Holzman TF, Chung CC, Edalji R, et al: Recombinant human prorenin from CHO cells: expression and purification. J Protein Chem. 9:663–672. 1990. View Article : Google Scholar : PubMed/NCBI
39	Wautier JL and Schmidt AM: Protein glycation: a firm link to endothelial cell dysfunction. Circ Res. 95:233–238. 2004. View Article : Google Scholar : PubMed/NCBI
40	Takahashi K, Yamamoto H, Hirose T, et al: Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy. Peptides. 31:1405–1408. 2010. View Article : Google Scholar : PubMed/NCBI
41	Huang J and Siragy HM: Glucose promotes the production of interleukine-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression. Endocrinology. 150:5557–5565. 2009. View Article : Google Scholar : PubMed/NCBI
42	Huang J and Siragy HM: Regulation of (pro)renin receptor expression by glucose-induced mitogen-activated protein kinase, nuclear factor-kappaB, and activator protein-1 signaling pathways. Endocrinology. 151:3317–3325. 2010. View Article : Google Scholar
43	Sennoune SR and Martinez-Zaguilan R: Vacuolar H⁺-ATPase signaling pathway in cancer. Curr Protein Pept Sci. 13:152–163. 2012.
44	Krop M, Lu X, Danser AH and Meima ME: The (pro)renin receptor. A decade of research: what have we learned? Pflugers Arch. 465:87–97. 2013. View Article : Google Scholar : PubMed/NCBI
45	Fukushima A, Kinugawa S, Homma T, et al: Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure. Int J Cardiol. 168:4313–4314. 2013. View Article : Google Scholar : PubMed/NCBI
46	Batenburg WW, Lu X, Leijten F, Maschke U, Muller DN and Danser AH: Renin- and prorenin-induced effects in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor: does (pro)renin-(pro)renin receptor interaction actually occur? Hypertension. 58:1111–1119. 2011. View Article : Google Scholar
47	Sakoda M, Ichihara A, Kaneshiro Y, et al: (Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells. Hypertens Res. 30:1139–1146. 2007. View Article : Google Scholar : PubMed/NCBI
48	Saris JJ, van den Eijnden MM, Lamers JM, Saxena PR, Schalekamp MA and Danser AH: Prorenin-induced myocyte proliferation: no role for intracellular angiotensin II. Hypertension. 39:573–577. 2002. View Article : Google Scholar : PubMed/NCBI
49	Uraoka M, Ikeda K, Nakagawa Y, et al: Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system. Biochem Biophys Res Commun. 390:1202–1207. 2009. View Article : Google Scholar : PubMed/NCBI
50	Kinouchi K, Ichihara A, Sano M, et al: The (pro)renin receptor/ATP6AP2 is essential for vacuolar H⁺-ATPase assembly in murine cardiomyocytes. Circ Res. 107:30–34. 2010. View Article : Google Scholar : PubMed/NCBI
51	Riediger F, Quack I, Qadri F, et al: Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol. 22:2193–2202. 2011. View Article : Google Scholar : PubMed/NCBI
52	Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S and Hopkins N: Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA. 101:12792–12797. 2004. View Article : Google Scholar : PubMed/NCBI
53	Liang P, Jones CA, Bisgrove BW, et al: Genomic characterization and expression analysis of the first nonmammalian renin genes from zebrafish and pufferfish. Physiol Genomics. 16:314–322. 2004. View Article : Google Scholar : PubMed/NCBI
54	Reudelhuber TL: The interaction between prorenin, renin and the (pro)renin receptor: time to rethink the role in hypertension. Curr Opin Nephrol Hypertens. 21:137–141. 2012. View Article : Google Scholar : PubMed/NCBI
55	Bader M: The (pro)renin receptor, (P)RR/ATP6AP2, a bifunctional protein? J Renin Angiotensin Aldosterone Syst. 9(Suppl 1): S52008.
56	Juillerat-Jeanneret L, Celerier J, Chapuis Bernasconi C, et al: Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br J Cancer. 90:1059–1068. 2004. View Article : Google Scholar : PubMed/NCBI
57	Rusin A, Krawczyk Z, Grynkiewicz G, Gogler A, Zawisza-Puchalka J and Szeja W: Synthetic derivatives of genistein, their properties and possible applications. Acta Biochim Pol. 57:23–34. 2010.PubMed/NCBI
58	Soucy NV, Parkinson HD, Sochaski MA and Borghoff SJ: Kinetics of genistein and its conjugated metabolites in pregnant Sprague-Dawley rats following single and repeated genistein administration. Toxicol Sci. 90:230–240. 2006. View Article : Google Scholar : PubMed/NCBI
59	Spinozzi F, Pagliacci MC, Migliorati G, et al: The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. Leuk Res. 18:431–439. 1994. View Article : Google Scholar : PubMed/NCBI
60	Su Y, Simmen FA, Xiao R and Simmen RC: Expression profiling of rat mammary epithelial cells reveals candidate signaling pathways in dietary protection from mammary tumors. Physiol Genomics. 30:8–16. 2007. View Article : Google Scholar : PubMed/NCBI
61	Zhang Y and Chen H: Genistein, an epigenome modifier during cancer prevention. Epigenetics. 6:888–891. 2011. View Article : Google Scholar : PubMed/NCBI
62	Gullett NP, Ruhul Amin AR, Bayraktar S, et al: Cancer prevention with natural compounds. Semin Oncol. 37:258–281. 2010. View Article : Google Scholar : PubMed/NCBI
63	Pavese JM, Farmer RL and Bergan RC: Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metastasis Rev. 29:465–482. 2010. View Article : Google Scholar : PubMed/NCBI
64	Rusin A, Zawisza-Puchalka J, Kujawa K, et al: Synthetic conjugates of genistein affecting proliferation and mitosis of cancer cells. Bioorg Med Chem. 19:295–305. 2011. View Article : Google Scholar : PubMed/NCBI
65	El-Rayes BF, Philip PA, Sarkar FH, et al: A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer. Invest New Drugs. 29:694–699. 2011. View Article : Google Scholar : PubMed/NCBI
66	McSheehy PM, Troy H, Kelland LR, Judson IR, Leach MO and Griffiths JR: Increased tumour extracellular pH induced by Bafilomycin A1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics. Eur J Cancer. 39:532–540. 2003. View Article : Google Scholar : PubMed/NCBI
67	Kinoshita K, Waritani T, Noto M, et al: Bafilomycin A1 induces apoptosis in PC12 cells independently of intracellular pH. FEBS Lett. 398:61–66. 1996. View Article : Google Scholar : PubMed/NCBI
68	Ohta T, Arakawa H, Futagami F, et al: Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1. J Pathol. 185:324–330. 1998. View Article : Google Scholar : PubMed/NCBI
69	Lee CM and Tannock IF: Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration. Br J Cancer. 94:863–869. 2006. View Article : Google Scholar : PubMed/NCBI
70	http://www.clinicaltrials.gov/ct2/results?term=bafilomycin&Search=Search. accessed 19/12/2013
71	Elmarakby AA, Ibrahim AS, Faulkner J, Mozaffari MS, Liou GI and Abdelsayed R: Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol. 55:149–156. 2011. View Article : Google Scholar : PubMed/NCBI
72	Zhong WW, Liu Y and Li CL: Mechanisms of genistein protection on pancreas cell damage in high glucose condition. Intern Med. 50:2129–2134. 2011. View Article : Google Scholar : PubMed/NCBI
73	Hettiarachchi KD, Zimmet PZ and Myers MA: The effects of repeated exposure to sub-toxic doses of plecomacrolide antibiotics on the endocrine pancreas. Food Chem Toxicol. 44:1966–1977. 2006. View Article : Google Scholar : PubMed/NCBI
74	Myers MA, Hettiarachchi KD, Ludeman JP, Wilson AJ, Wilson CR and Zimmet PZ: Dietary microbial toxins and type 1 diabetes. Ann NY Acad Sci. 1005:418–422. 2003. View Article : Google Scholar : PubMed/NCBI
75	Lammi N, Karvonen M and Tuomilehto J: Do microbes have a causal role in type 1 diabetes? Med Sci Monit. 11:RA63–RA69. 2005.PubMed/NCBI
76	Klein CB and King AA: Genistein genotoxicity: critical considerations of in vitro exposure dose. Toxicol Appl Pharmacol. 224:1–11. 2007. View Article : Google Scholar : PubMed/NCBI
77	Labbaye C, Spinello I, Quaranta MT, et al: A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat Cell Biol. 10:788–801. 2008. View Article : Google Scholar : PubMed/NCBI
78	Zhang W and Liu HT: MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12:9–18. 2002. View Article : Google Scholar
79	Barker N and Clevers H: Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. 5:997–1014. 2006. View Article : Google Scholar : PubMed/NCBI
80	Sennoune SR, Luo D and Martinez-Zaguilan R: Plasmalemmal vacuolar-type H⁺-ATPase in cancer biology. Cell Biochem Biophys. 40:185–206. 2004. View Article : Google Scholar
81	Huang Y, Noble NA, Zhang J, Xu C and Border WA: Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int. 72:45–52. 2007. View Article : Google Scholar : PubMed/NCBI
82	Balakumar P and Jagadeesh G: Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders. Hypertens Res. 34:1161–1170. 2011. View Article : Google Scholar : PubMed/NCBI