Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA9MYD5)

DOT Name	Aquaporin-4 (AQP4)
Synonyms	AQP-4; Mercurial-insensitive water channel; MIWC; WCH4
Gene Name	AQP4
Related Disease	Adult glioblastoma ( ) Alzheimer disease ( ) Amyloidosis ( ) Astrocytoma ( ) Autism ( ) Autoimmune disease ( ) Breast cancer ( ) Breast carcinoma ( ) Cerebral infarction ( ) Cone-rod dystrophy 2 ( ) Creutzfeldt Jacob disease ( ) Demyelinating disease of central nervous system ( ) Depression ( ) Diabetic retinopathy ( ) Duchenne muscular dystrophy ( ) Encephalitis ( ) Epilepsy ( ) Glaucoma/ocular hypertension ( ) Lung adenocarcinoma ( ) Malaria ( ) Malignant glioma ( ) Meniere disease ( ) Meningioma ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Parkinson disease ( ) Pseudotumor cerebri ( ) Retinopathy ( ) Sjogren syndrome ( ) Subarachnoid hemorrhage ( ) Temporal lobe epilepsy ( ) Trichohepatoenteric syndrome ( ) Type-1/2 diabetes ( ) Uveitis ( ) Brain disease ( ) Eclampsia ( ) Intracerebral hemorrhage ( ) Stroke ( ) High blood pressure ( ) Primary biliary cholangitis ( ) Status epilepticus seizure ( ) Amyotrophic lateral sclerosis ( ) Hand, foot and mouth disease ( ) Hydrocephalus ( ) Inflammation ( ) Intellectual disability ( ) Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting ( ) Neuromyelitis optica ( ) Retinal vein occlusion ( )
UniProt ID	AQP4_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3GD8
Pfam ID	PF00230
Sequence	MSDRPTARRWGKCGPLCTRENIMVAFKGVWTQAFWKAVTAEFLAMLIFVLLSLGSTINWG GTEKPLPVDMVLISLCFGLSIATMVQCFGHISGGHINPAVTVAMVCTRKISIAKSVFYIA AQCLGAIIGAGILYLVTPPSVVGGLGVTMVHGNLTAGHGLLVELIITFQLVFTIFASCDS KRTDVTGSIALAIGFSVAIGHLFAINYTGASMNPARSFGPAVIMGNWENHWIYWVGPIIG AVLAGGLYEYVFCPDVEFKRRFKEAFSKAAQQTKGSYMEVEDNRSQVETDDLILKPGVVH VIDVDRGEEKKGKDQSGEVLSSV
Function	Forms a water-specific channel. Plays an important role in brain water homeostasis. It is involved in glymphatic solute transport and is required for a normal rate of water exchange across the blood brain interface. Required for normal levels of cerebrospinal fluid influx into the brain cortex and parenchyma along paravascular spaces that surround penetrating arteries, and for normal drainage of interstitial fluid along paravenous drainage pathways. Thereby, it is required for normal clearance of solutes from the brain interstitial fluid, including soluble beta-amyloid peptides derived from APP. Plays a redundant role in urinary water homeostasis and urinary concentrating ability.
Tissue Specificity	Detected in skeletal muscle . Detected in stomach, along the glandular base region of the fundic gland (at protein level) . Detected in brain, lung and skeletal muscle, and at much lower levels in heart and ovary .
KEGG Pathway	Vasopressin-regulated water reabsorption (hsa04962 ) Bile secretion (hsa04976 )
Reactome Pathway	Passive transport by Aquaporins (R-HSA-432047 ) Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Autoimmune disease	DISORMTM	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[8]
Cone-rod dystrophy 2	DISX2RWY	Strong	Altered Expression	[9]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[10]
Demyelinating disease of central nervous system	DIS9H7BS	Strong	Altered Expression	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[13]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[14]
Encephalitis	DISLD1RL	Strong	Biomarker	[15]
Epilepsy	DISBB28L	Strong	Biomarker	[16]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Altered Expression	[17]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[18]
Malaria	DISQ9Y50	Strong	Biomarker	[19]
Malignant glioma	DISFXKOV	Strong	Biomarker	[20]
Meniere disease	DISC5R5F	Strong	Genetic Variation	[21]
Meningioma	DISPT4TG	Strong	Altered Expression	[22]
Neoplasm	DISZKGEW	Strong	Altered Expression	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[24]
Parkinson disease	DISQVHKL	Strong	Biomarker	[25]
Pseudotumor cerebri	DISLLY7S	Strong	Altered Expression	[26]
Retinopathy	DISB4B0F	Strong	Biomarker	[27]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[28]
Subarachnoid hemorrhage	DISI7I8Y	Strong	Altered Expression	[29]
Temporal lobe epilepsy	DISNOPXX	Strong	Biomarker	[30]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[31]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[32]
Uveitis	DISV0RYS	Strong	Biomarker	[33]
Brain disease	DIS6ZC3X	moderate	Biomarker	[34]
Eclampsia	DISWPO8U	moderate	Altered Expression	[35]
Intracerebral hemorrhage	DISC81BT	moderate	Biomarker	[36]
Stroke	DISX6UHX	moderate	Altered Expression	[37]
High blood pressure	DISY2OHH	Disputed	Biomarker	[38]
Primary biliary cholangitis	DIS43E0O	Disputed	Biomarker	[39]
Status epilepticus seizure	DISY3BIC	Disputed	Biomarker	[40]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[41]
Hand, foot and mouth disease	DISKJHLL	Limited	Biomarker	[42]
Hydrocephalus	DISIZUF7	Limited	Altered Expression	[29]
Inflammation	DISJUQ5T	Limited	Biomarker	[43]
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[44]
Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting	DISDV9RK	Limited	Autosomal recessive	[44]
Neuromyelitis optica	DISBFGKL	Limited	Unknown	[44]
Retinal vein occlusion	DISSVWOE	Limited	Biomarker	[45]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Aquaporin-4 (AQP4) increases the response to substance of Olanzapine.	[53]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Aquaporin-4 (AQP4).	[46]
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7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Aquaporin-4 (AQP4).	[47]
Cannabidiol	DM0659E	Approved	Cannabidiol affects the expression of Aquaporin-4 (AQP4).	[48]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Aquaporin-4 (AQP4).	[49]
Ammonia	DMOEVK6	Approved	Ammonia decreases the expression of Aquaporin-4 (AQP4).	[50]
Guanfacine extended release	DMB1CZ8	Approved	Guanfacine extended release affects the expression of Aquaporin-4 (AQP4).	[48]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Aquaporin-4 (AQP4).	[51]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Aquaporin-4 (AQP4).	[52]
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⏷ Show the Full List of 7 Drug(s)

References

1	Gamabufotalin induces a negative feedback loop connecting ATP1A3 expression and the AQP4 pathway to promote temozolomide sensitivity in glioblastoma cells by targeting the amino acid Thr794.Cell Prolif. 2020 Jan;53(1):e12732. doi: 10.1111/cpr.12732. Epub 2019 Nov 20.
2	Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease.Cells. 2019 Jan 27;8(2):90. doi: 10.3390/cells8020090.
3	Long-term consumption of alcohol exacerbates neural lesions by destroying the functional integrity of the blood-brain barrier.Drug Chem Toxicol. 2022 Jan;45(1):231-238. doi: 10.1080/01480545.2019.1681444. Epub 2019 Nov 20.
4	The value of multi ultrahigh-b-value DWI in grading cerebral astrocytomas and its association with aquaporin-4.Br J Radiol. 2018 Jun;91(1086):20170696. doi: 10.1259/bjr.20170696. Epub 2018 Mar 20.
5	Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism.Synapse. 2008 Jul;62(7):501-7. doi: 10.1002/syn.20519.
6	Autoimmune glial fibrillary acidic protein astrocytopathy.Curr Opin Neurol. 2019 Jun;32(3):452-458. doi: 10.1097/WCO.0000000000000676.
7	Aquaporin-4 antibody positive short transverse myelitis associated with breast cancer.Mult Scler Relat Disord. 2019 May;30:119-122. doi: 10.1016/j.msard.2019.02.011. Epub 2019 Feb 8.
8	Goreisan Prevents Brain Edema after Cerebral Ischemic Stroke by Inhibiting Aquaporin 4 Upregulation in Mice.J Stroke Cerebrovasc Dis. 2018 Mar;27(3):758-763. doi: 10.1016/j.jstrokecerebrovasdis.2017.10.010. Epub 2017 Nov 16.
9	Aquaporin-4 expression dynamically varies after acute spinal cord injury-induced disruption of blood spinal cord barrier in rats.Neuropathology. 2019 Jun;39(3):181-186. doi: 10.1111/neup.12539. Epub 2019 Mar 27.
10	Enhanced Aquaporin-4 immunoreactivity in sporadic Creutzfeldt-Jakob disease.Neuropathology. 2007 Aug;27(4):314-23. doi: 10.1111/j.1440-1789.2007.00781.x.
11	Association Between the Single Nucleotide Polymorphism and the Level of Aquaporin-4 Protein Expression in Han and Minority Chinese with Inflammatory Demyelinating Diseases of the Central Nervous System.Mol Neurobiol. 2016 Jul;53(5):2878-2885. doi: 10.1007/s12035-015-9171-9. Epub 2015 Apr 18.
12	Mechanism of depression as a risk factor in the development of Alzheimer's disease: the function of AQP4 and the glymphatic system.Psychopharmacology (Berl). 2017 Feb;234(3):365-379. doi: 10.1007/s00213-016-4473-9. Epub 2016 Nov 12.
13	Aquaporin 4 knockdown exacerbates streptozotocin-induced diabetic retinopathy through aggravating inflammatory response.Exp Eye Res. 2012 May;98:37-43. doi: 10.1016/j.exer.2012.02.013. Epub 2012 Mar 16.
14	Changes in skeletal muscle expression of AQP1 and AQP4 in dystrophinopathy and dysferlinopathy patients.Acta Neuropathol. 2008 Sep;116(3):235-46. doi: 10.1007/s00401-008-0369-z. Epub 2008 Apr 8.
15	Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.Eur J Neurol. 2019 Jan;26(1):168-174. doi: 10.1111/ene.13790. Epub 2018 Sep 24.
16	Astrocytes and Glutamine Synthetase in Epileptogenesis.J Neurosci Res. 2019 Nov;97(11):1345-1362. doi: 10.1002/jnr.24267. Epub 2018 Jul 18.
17	Changes in retinal aquaporin-9 (AQP9) expression in glaucoma.Biosci Rep. 2013 Apr 23;33(2):e00035. doi: 10.1042/BSR20130005.
18	Neuromyelitis optica spectrum disorder after treatment with pembrolizumab.Mult Scler Relat Disord. 2020 Jan;37:101447. doi: 10.1016/j.msard.2019.101447. Epub 2019 Oct 14.
19	Protective role of brain water channel AQP4 in murine cerebral malaria.Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1035-40. doi: 10.1073/pnas.1220566110. Epub 2012 Dec 31.
20	AQP4 Aggregation State Is a Determinant for Glioma Cell Fate.Cancer Res. 2019 May 1;79(9):2182-2194. doi: 10.1158/0008-5472.CAN-18-2015. Epub 2019 Mar 15.
21	Polymorphisms in genes encoding aquaporins 4 and 5 and estrogen receptor in patients with Mnire's disease and sudden sensorineural hearing loss.Life Sci. 2013 Mar 21;92(10):541-6. doi: 10.1016/j.lfs.2013.01.019. Epub 2013 Jan 24.
22	Correlation Between Aquaporin 4 Expression and Different DWI Parameters in Grade I Meningioma.Mol Imaging Biol. 2017 Feb;19(1):138-142. doi: 10.1007/s11307-016-0978-1.
23	Radiation-Induced Changes in Tumor Vessels and Microenvironment Contribute to Therapeutic Resistance in Glioblastoma.Front Oncol. 2019 Nov 15;9:1259. doi: 10.3389/fonc.2019.01259. eCollection 2019.
24	Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain metastases.Oncotarget. 2019 Oct 29;10(59):6334-6348. doi: 10.18632/oncotarget.27274. eCollection 2019 Oct 29.
25	Aquaporin-4 deficiency reduces TGF-1 in mouse midbrains and exacerbates pathology in experimental Parkinson's disease.J Cell Mol Med. 2019 Apr;23(4):2568-2582. doi: 10.1111/jcmm.14147. Epub 2019 Jan 25.
26	Cerebral microvascular abnormalities in patients with idiopathic intracranial hypertension.Brain Res. 2018 May 1;1686:72-82. doi: 10.1016/j.brainres.2018.02.017. Epub 2018 Feb 22.
27	Potential role of the methylation of VEGF gene promoter in response to hypoxia in oxygen-induced retinopathy: beneficial effect of the absence of AQP4.J Cell Mol Med. 2018 Jan;22(1):613-627. doi: 10.1111/jcmm.13348. Epub 2017 Sep 22.
28	Syringomyelia-like syndrome in neuromyelitis optica spectrum disorder complicated with Sjogren's syndrome: a case report.BMC Neurol. 2018 Oct 9;18(1):168. doi: 10.1186/s12883-018-1170-9.
29	The dynamic expression of aquaporins 1 and 4 in rats with hydrocephalus induced by subarachnoid haemorrhage.Folia Neuropathol. 2019;57(2):182-195. doi: 10.5114/fn.2019.86296.
30	Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex.Neurobiol Dis. 2019 Sep;129:93-101. doi: 10.1016/j.nbd.2019.05.003. Epub 2019 May 9.
31	Devic's index case: A critical reappraisal - AQP4-IgG-mediated neuromyelitis optica spectrum disorder, or rather MOG encephalomyelitis?.J Neurol Sci. 2019 Dec 15;407:116396. doi: 10.1016/j.jns.2019.07.014. Epub 2019 Jul 11.
32	Altered expression of aquaporins 1 and 4 coincides with neurodegenerative events in retinas of spontaneously diabetic Torii rats.Exp Eye Res. 2010 Jan;90(1):17-25. doi: 10.1016/j.exer.2009.09.003. Epub 2009 Sep 11.
33	Differential regulations of AQP4 and Kir4.1 by triamcinolone acetonide and dexamethasone in the healthy and inflamed retina.Invest Ophthalmol Vis Sci. 2011 Aug 11;52(9):6340-7. doi: 10.1167/iovs.11-7675.
34	Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease.Cell Rep. 2019 Jun 25;27(13):3860-3872.e4. doi: 10.1016/j.celrep.2019.05.097.
35	Magnesium sulfate attenuates brain edema by lowering AQP4 expression and inhibits glia-mediated neuroinflammation in a rodent model of eclampsia.Behav Brain Res. 2019 May 17;364:403-412. doi: 10.1016/j.bbr.2017.12.031. Epub 2017 Dec 27.
36	Loss of AQP4 polarized localization with loss of -dystroglycan immunoreactivity may induce brain edema following intracerebral hemorrhage.Neurosci Lett. 2015 Feb 19;588:42-8. doi: 10.1016/j.neulet.2014.12.053. Epub 2014 Dec 27.
37	Circulating Aquaporin-4 as A biomarker of early neurological improvement in stroke patients: A pilot study.Neurosci Lett. 2020 Jan 1;714:134580. doi: 10.1016/j.neulet.2019.134580. Epub 2019 Oct 28.
38	Expression of aquaporins 1 and 4 in the brain of spontaneously hypertensive rats.Brain Res. 2010 Apr 14;1325:155-63. doi: 10.1016/j.brainres.2010.02.023. Epub 2010 Feb 12.
39	Role of aquaporin-4 in the development of brain oedema in liver failure.J Hepatol. 2010 Jul;53(1):91-7. doi: 10.1016/j.jhep.2010.02.020. Epub 2010 Apr 1.
40	Astroglial loss and edema formation in the rat piriform cortex and hippocampus following pilocarpine-induced status epilepticus.J Comp Neurol. 2010 Nov 15;518(22):4612-28. doi: 10.1002/cne.22482.
41	The potential roles of aquaporin 4 in amyotrophic lateral sclerosis.Neurol Sci. 2019 Aug;40(8):1541-1549. doi: 10.1007/s10072-019-03877-5. Epub 2019 Apr 13.
42	Distinct expression and clinical value of aquaporin 4 in children with hand, foot and mouth disease caused by enterovirus 71.J Med Virol. 2022 Feb;94(2):587-593. doi: 10.1002/jmv.25475. Epub 2019 Apr 23.
43	CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder.Ann Clin Transl Neurol. 2017 May 9;4(6):369-380. doi: 10.1002/acn3.418. eCollection 2017 Jun.
44	Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
45	Effects of intravitreal triamcinolone acetonide on retinal gene expression in a rat model of central retinal vein occlusion.Graefes Arch Clin Exp Ophthalmol. 2011 Aug;249(8):1175-83. doi: 10.1007/s00417-011-1683-z. Epub 2011 Apr 13.
46	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
47	In vitro study of transporters involved in intestinal absorption of inorganic arsenic. Chem Res Toxicol. 2012 Feb 20;25(2):446-53. doi: 10.1021/tx200491f. Epub 2012 Jan 26.
48	Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo-A Randomized, Placebo-controlled, Double-blind Controlled Trial. Inflamm Bowel Dis. 2019 May 4;25(6):1006-1018. doi: 10.1093/ibd/izz017.
49	Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
50	Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure. Metab Brain Dis. 2010 Mar;25(1):17-21.
51	Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
52	From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
53	Different impacts of aquaporin 4 and MAOA allele variation among olanzapine, risperidone, and paliperidone in schizophrenia. J Clin Psychopharmacol. 2012 Jun;32(3):394-7. doi: 10.1097/JCP.0b013e31825370f4.