Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0IABVV)

• DOT Name: Renin receptor (ATP6AP2)
• Synonyms: ATPase H(+)-transporting lysosomal accessory protein 2; ATPase H(+)-transporting lysosomal-interacting protein 2; ER-localized type I transmembrane adapter; Embryonic liver differentiation factor 10; N14F; Renin/prorenin receptor; Vacuolar ATP synthase membrane sector-associated protein M8-9; ATP6M8-9; V-ATPase M8.9 subunit
• Gene Name: ATP6AP2
• Related Disease:
  ATP6AP2-related disorder
  Pancreatic ductal carcinoma
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Atrial fibrillation
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Congenital disorder of glycosylation, type IIr
  Depression
  Diabetic retinopathy
  Dilated cardiomyopathy 1A
  Ductal breast carcinoma in situ
  Endometrial cancer
  Endometrial carcinoma
  Epilepsy
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Myocardial infarction
  Neoplasm
  Nephropathy
  Non-insulin dependent diabetes
  Obesity
  Obstructive sleep apnea
  Parkinson disease
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Syndromic X-linked intellectual disability Hedera type
  Arteriosclerosis
  Atherosclerosis
  Bacterial infection
  Cardiac failure
  Chronic renal failure
  Congestive heart failure
  Diabetic kidney disease
  Parkinsonian disorder
  X-linked parkinsonism-spasticity syndrome
  Cardiovascular disease
  Colorectal carcinoma
  Coronary heart disease
  Intellectual disability
  X-linked intellectual disability
• UniProt ID: RENR_HUMAN
• PDB ID: 3LBS; 3LC8; 6WLW; 6WM2; 6WM3; 6WM4; 7U4T
• Pfam ID: PF07850
• Sequence:
  MAVFVVLLALVAGVLGNEFSILKSPGSVVFRNGNWPIPGERIPDVAALSMGFSVKEDLSW
  PGLAVGNLFHRPRATVMVMVKGVNKLALPPGSVISYPLENAVPFSLDSVANSIHSLFSEE
  TPVVLQLAPSEERVYMVGKANSVFEDLSVTLRQLRNRLFQENSVLSSLPLNSLSRNNEVD
  LLFLSELQVLHDISSLLSRHKHLAKDHSPDLYSLELAGLDEIGKRYGEDSEQFRDASKIL
  VDALQKFADDMYSLYGGNAVVELVTVKSFDTSLIRKTRTILEAKQAKNPASPYNLAYKYN
  FEYSVVFNMVLWIMIALALAVIITSYNIWNMDPGYDSIIYRMTNQKIRMD
• Function: Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system. 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, may also play a role in the renin-angiotensin system (RAS). Through its function in V-type ATPase (v-ATPase) assembly and acidification of the lysosome it regulates protein degradation and may control different signaling pathways important for proper brain development, synapse morphology and synaptic transmission.
• Tissue Specificity: Expressed in brain, heart, placenta, liver, kidney and pancreas. Barely detectable in lung and skeletal muscles. In the kidney cortex it is restricted to the mesangium of glomeruli. In the coronary and kidney artery it is expressed in the subendothelium, associated to smooth muscles where it colocalizes with REN. Expressed in vascular structures and by syncytiotrophoblast cells in the mature fetal placenta.
• KEGG Pathway: Renin-angiotensin system (hsa04614)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)
• BioCyc Pathway: MetaCyc:MONOMER66-34369

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ATP6AP2-related disorder	DISJP8P3	Definitive	X-linked	[1]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[9]
Congenital disorder of glycosylation, type IIr	DISF9AZ9	Strong	X-linked	[10]
Depression	DIS3XJ69	Strong	Altered Expression	[11]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[12]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[8]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[8]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[13]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[13]
Epilepsy	DISBB28L	Strong	Genetic Variation	[14]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[17]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Nephropathy	DISXWP4P	Strong	Biomarker	[20]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[21]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Obstructive sleep apnea	DIS0SVD1	Strong	Altered Expression	[22]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[17]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[23]
Prostate cancer	DISF190Y	Strong	Altered Expression	[24]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[24]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[25]
Syndromic X-linked intellectual disability Hedera type	DISLK2OE	Strong	X-linked	[14]
Arteriosclerosis	DISK5QGC	moderate	Biomarker	[26]
Atherosclerosis	DISMN9J3	moderate	Biomarker	[26]
Bacterial infection	DIS5QJ9S	moderate	Genetic Variation	[27]
Cardiac failure	DISDC067	moderate	Biomarker	[9]
Chronic renal failure	DISGG7K6	moderate	Altered Expression	[28]
Congestive heart failure	DIS32MEA	moderate	Biomarker	[9]
Diabetic kidney disease	DISJMWEY	moderate	Altered Expression	[29]
Parkinsonian disorder	DISHGY45	moderate	Biomarker	[30]
X-linked parkinsonism-spasticity syndrome	DISQ75VN	Moderate	X-linked	[31]
Cardiovascular disease	DIS2IQDX	Limited	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[32]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[33]
Intellectual disability	DISMBNXP	Limited	Biomarker	[34]
X-linked intellectual disability	DISYJBY3	Limited	Genetic Variation	[35]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Renin receptor (ATP6AP2).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Renin receptor (ATP6AP2).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Renin receptor (ATP6AP2).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Renin receptor (ATP6AP2).	[39]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Renin receptor (ATP6AP2).	[40]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Renin receptor (ATP6AP2).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Renin receptor (ATP6AP2).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Renin receptor (ATP6AP2).	[44]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Renin receptor (ATP6AP2).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Renin receptor (ATP6AP2).	[46]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Renin receptor (ATP6AP2).	[47]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Renin receptor (ATP6AP2).	[48]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Renin receptor (ATP6AP2).	[42]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Correction: Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis.Oncotarget. 2019 Jan 11;10(4):558. doi: 10.18632/oncotarget.26597. eCollection 2019 Jan 11.
• [3] (Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma-Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis.Cancers (Basel). 2019 Jun 24;11(6):881. doi: 10.3390/cancers11060881.
• [4] (Pro)renin receptor is crucial for glioma development via the Wnt/-catenin signaling pathway.J Neurosurg. 2017 Oct;127(4):819-828. doi: 10.3171/2016.9.JNS16431. Epub 2017 Jan 6.
• [5] The (pro)renin receptor in health and disease.Nat Rev Nephrol. 2019 Nov;15(11):693-712. doi: 10.1038/s41581-019-0160-5.
• [6] Long-term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization-activated cyclic nucleotide gated channel overexpression.J Cardiovasc Electrophysiol. 2019 Feb;30(2):242-252. doi: 10.1111/jce.13772. Epub 2018 Nov 5.
• [7] Increased expression of TLR2 in CD4(+) T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications.Eur J Immunol. 2015 Sep;45(9):2683-93. doi: 10.1002/eji.201445219. Epub 2015 Jun 26.
• [8] CAPER, a novel regulator of human breast cancer progression.Cell Cycle. 2014;13(8):1256-64. doi: 10.4161/cc.28156. Epub 2014 Feb 17.
• [9] (Pro)renin Receptor Blockade Ameliorates Heart Failure Caused by Chronic Kidney Disease.J Card Fail. 2019 Apr;25(4):286-300. doi: 10.1016/j.cardfail.2019.02.009. Epub 2019 Feb 13.
• [10] Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. J Exp Med. 2017 Dec 4;214(12):3707-3729. doi: 10.1084/jem.20170453. Epub 2017 Nov 10.
• [11] Effect of heme oxygenase 1 and renin/prorenin receptor on oxidized low-density lipoprotein-induced human umbilical vein endothelial cells.Exp Ther Med. 2019 Sep;18(3):1752-1760. doi: 10.3892/etm.2019.7769. Epub 2019 Jul 12.
• [12] (Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.J Diabetes Investig. 2019 Jan;10(1):6-17. doi: 10.1111/jdi.12842. Epub 2018 May 13.
• [13] Expression of renin-angiotensin system (RAS) components in endometrial cancer.Endocr Connect. 2017 Jan;6(1):9-19. doi: 10.1530/EC-16-0082. Epub 2016 Dec 12.
• [14] A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet. 2005 Apr 15;14(8):1019-27. doi: 10.1093/hmg/ddi094. Epub 2005 Mar 3.
• [15] Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma.Hepatology. 2015 Oct;62(4):1122-31. doi: 10.1002/hep.27923. Epub 2015 Jul 3.
• [16] MicroRNA-140-3p inhibits proliferation, migration and invasion of lung cancer cells by targeting ATP6AP2. Int J Clin Exp Pathol. 2015 Oct 1;8(10):12845-52. eCollection 2015.
• [17] Renin-angiotensin system gene expression and neurodegenerative diseases.J Renin Angiotensin Aldosterone Syst. 2016 Sep 9;17(3):1470320316666750. doi: 10.1177/1470320316666750. Print 2016 Jul.
• [18] (Pro)renin receptor expression in myocardial infarction in transgenic mice expressing rat tonin.Int J Biol Macromol. 2018 Mar;108:817-825. doi: 10.1016/j.ijbiomac.2017.10.179. Epub 2017 Nov 2.
• [19] Pathogen Molecular Pattern Receptor Agonists: Treating Cancer by Mimicking Infection.Clin Cancer Res. 2019 Nov 1;25(21):6283-6294. doi: 10.1158/1078-0432.CCR-18-1800. Epub 2019 May 23.
• [20] Superimposing a high-fat diet on Schistosoma mansoni infection affects renin-angiotensin system components in the mouse kidney.Rev Soc Bras Med Trop. 2019 Mar 7;52:e20180371. doi: 10.1590/0037-8682-0371-2018.
• [21] Aliskiren directly improves endothelial progenitor cell function from Type II diabetic patients.Eur J Clin Invest. 2016 Jun;46(6):544-54. doi: 10.1111/eci.12632. Epub 2016 Apr 30.
• [22] Elevated plasma soluble (pro)renin receptor levels are associated with left ventricular remodeling and renal function in chronic heart failure patients with reduced ejection fraction.Peptides. 2019 Jan;111:152-157. doi: 10.1016/j.peptides.2018.04.010. Epub 2018 Apr 13.
• [23] Distinct signal transduction pathways downstream of the (P)RR revealed by microarray and ChIP-chip analyses.PLoS One. 2013;8(3):e57674. doi: 10.1371/journal.pone.0057674. Epub 2013 Mar 4.
• [24] V-ATPase-associated prorenin receptor is upregulated in prostate cancer after PTEN loss.Oncotarget. 2019 Aug 13;10(48):4923-4936. doi: 10.18632/oncotarget.27075. eCollection 2019 Aug 13.
• [25] Evaluation of Renin and Soluble (Pro)renin Receptor in Patients with IPF. A Comparison with Hypersensitivity Pneumonitis.Lung. 2019 Dec;197(6):715-720. doi: 10.1007/s00408-019-00278-5. Epub 2019 Oct 15.
• [26] A functional variant in the CARD4 gene and risk of premature coronary heart disease.Int J Immunogenet. 2006 Aug;33(4):307-11. doi: 10.1111/j.1744-313X.2006.00618.x.
• [27] Functional polymorphisms of innate immunity receptors are not risk factors for the non-SBP type bacterial infections in cirrhosis.Liver Int. 2018 Jul;38(7):1242-1252. doi: 10.1111/liv.13664. Epub 2018 Jan 17.
• [28] Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy.Peptides. 2010 Jul;31(7):1405-8. doi: 10.1016/j.peptides.2010.04.003. Epub 2010 Apr 10.
• [29] (Pro)renin receptor contributes to renal mitochondria dysfunction, apoptosis and fibrosis in diabetic mice.Sci Rep. 2019 Aug 12;9(1):11667. doi: 10.1038/s41598-019-47055-1.
• [30] Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Mol Genet. 2013 Aug 15;22(16):3259-68. doi: 10.1093/hmg/ddt180. Epub 2013 Apr 16.
• [31] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [32] (Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations.Br J Cancer. 2019 Jan;120(2):229-237. doi: 10.1038/s41416-018-0350-0. Epub 2018 Dec 17.
• [33] A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals.J Hypertens. 2011 Mar;29(3):509-19. doi: 10.1097/HJH.0b013e328341d117.
• [34] Vaccine Coverage among Children with and without Intellectual Disabilities in the UK: Cross Sectional Study.BMC Public Health. 2019 Jun 13;19(1):748. doi: 10.1186/s12889-019-7106-5.
• [35] Prorenin receptor in kidney development.Pediatr Nephrol. 2017 Mar;32(3):383-392. doi: 10.1007/s00467-016-3365-x. Epub 2016 May 9.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [38] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [39] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [40] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [41] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [42] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [43] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [44] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [45] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [46] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [47] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [48] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.