Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQLBKK6)

DOT Name	Aquaporin-2 (AQP2)
Synonyms	AQP-2; ADH water channel; Aquaporin-CD; AQP-CD; Collecting duct water channel protein; WCH-CD; Water channel protein for renal collecting duct
Gene Name	AQP2
Related Disease	Nocturia ( ) Advanced cancer ( ) Autosomal dominant polycystic kidney disease ( ) Cardiac failure ( ) Cardiomyopathy ( ) Cholestasis ( ) Chronic renal failure ( ) Congestive heart failure ( ) Diabetes insipidus, nephrogenic, autosomal ( ) Diabetic kidney disease ( ) End-stage renal disease ( ) Endometrial cancer ( ) Endometriosis ( ) Episodic kinesigenic dyskinesia 1 ( ) Familial hypocalciuric hypercalcemia 1 ( ) High blood pressure ( ) Hypercalcaemia ( ) Hypophosphatemia ( ) Idiopathic cardiomyopathy ( ) Kidney failure ( ) Nephrogenic syndrome of inappropriate antidiuresis ( ) Nephropathy ( ) Nephrotic syndrome ( ) Polycystic kidney disease ( ) Variegate porphyria ( ) Adrenoleukodystrophy ( ) Allergic rhinitis ( ) Chronic otitis media ( ) Liver cirrhosis ( ) Sensorineural hearing loss disorder ( ) Nephrogenic diabetes insipidus ( ) Endolymphatic hydrops ( ) Endometrial carcinoma ( ) Metabolic disorder ( ) Central diabetes insipidus ( ) Chronic kidney disease ( ) Intellectual disability ( ) Meniere disease ( ) Non-insulin dependent diabetes ( ) Popliteal pterygium syndrome ( ) Renal fibrosis ( )
UniProt ID	AQP2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4NEF; 4OJ2; 6QF5; 8GCL; 8GHJ; 8OEE
Pfam ID	PF00230
Sequence	MWELRSIAFSRAVFAEFLATLLFVFFGLGSALNWPQALPSVLQIAMAFGLGIGTLVQALG HISGAHINPAVTVACLVGCHVSVLRAAFYVAAQLLGAVAGAALLHEITPADIRGDLAVNA LSNSTTAGQAVTVELFLTLQLVLCIFASTDERRGENPGTPALSIGFSVALGHLLGIHYTG CSMNPARSLAPAVVTGKFDDHWVFWIGPLVGAILGSLLYNYVLFPPAKSLSERLAVLKGL EPDTDWEEREVRRRQSVELHSPQSLPRGTKA
Function	Forms a water-specific channel that provides the plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. Plays an essential role in renal water homeostasis.
Tissue Specificity	Expressed in collecting tubules in kidney medulla (at protein level) . Detected in kidney .
KEGG Pathway	Vasopressin-regulated water reabsorption (hsa04962 )
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

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Nocturia	DISD1F1J	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Altered Expression	[4]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[5]
Cholestasis	DISDJJWE	Strong	Biomarker	[6]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[7]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Diabetes insipidus, nephrogenic, autosomal	DISC9CNV	Strong	Autosomal dominant	[9]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[10]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[7]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[11]
Endometriosis	DISX1AG8	Strong	Altered Expression	[12]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[3]
Familial hypocalciuric hypercalcemia 1	DISPW6O5	Strong	Altered Expression	[13]
High blood pressure	DISY2OHH	Strong	Altered Expression	[14]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[15]
Hypophosphatemia	DIS9DZYF	Strong	Biomarker	[16]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Biomarker	[5]
Kidney failure	DISOVQ9P	Strong	Altered Expression	[17]
Nephrogenic syndrome of inappropriate antidiuresis	DISRQBIJ	Strong	Genetic Variation	[18]
Nephropathy	DISXWP4P	Strong	Altered Expression	[19]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[20]
Polycystic kidney disease	DISWS3UY	Strong	Altered Expression	[3]
Variegate porphyria	DIS8OK5W	Strong	Altered Expression	[21]
Adrenoleukodystrophy	DISTUD1F	moderate	Genetic Variation	[22]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[23]
Chronic otitis media	DIS3P3TG	moderate	Altered Expression	[24]
Liver cirrhosis	DIS4G1GX	moderate	Altered Expression	[25]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[26]
Nephrogenic diabetes insipidus	DISKNSJK	Supportive	Autosomal dominant	[27]
Endolymphatic hydrops	DISUPJBC	Disputed	Biomarker	[28]
Endometrial carcinoma	DISXR5CY	Disputed	Altered Expression	[11]
Metabolic disorder	DIS71G5H	Disputed	Biomarker	[29]
Central diabetes insipidus	DISJ4P9O	Limited	Biomarker	[30]
Chronic kidney disease	DISW82R7	Limited	Altered Expression	[31]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[32]
Meniere disease	DISC5R5F	Limited	Altered Expression	[33]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[34]
Popliteal pterygium syndrome	DISRS4H8	Limited	Biomarker	[35]
Renal fibrosis	DISMHI3I	Limited	Altered Expression	[19]
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⏷ Show the Full List of 41 Disease(s)

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
Desoxycorticosterone acetate	DMS0AFE	Approved	Aquaporin-2 (AQP2) increases the Hypertension ADR of Desoxycorticosterone acetate.	[41]
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3 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-2 (AQP2).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Aquaporin-2 (AQP2).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aquaporin-2 (AQP2).	[40]
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2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Aquaporin-2 (AQP2).	[37]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine decreases the expression of Aquaporin-2 (AQP2).	[38]
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References

1	Evaluation of Urinary Aquaporin 2 and Plasma Copeptin as Biomarkers of Effectiveness of Desmopressin Acetate for the Treatment of Monosymptomatic Nocturnal Enuresis.J Urol. 2017 Oct;198(4):921-927. doi: 10.1016/j.juro.2017.04.088. Epub 2017 Apr 28.
2	L-Carnitine Ameliorates the Decrease of Aquaporin 2 Levels in Rats with Cisplatin-Induced Kidney Injury.Nephron. 2017;135(4):315-325. doi: 10.1159/000455052. Epub 2017 Feb 4.
3	Steviol slows renal cyst growth by reducing AQP2 expression and promoting AQP2 degradation.Biomed Pharmacother. 2018 May;101:754-762. doi: 10.1016/j.biopha.2018.02.139. Epub 2018 Mar 22.
4	Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure.Kidney Int. 2004 Oct;66(4):1387-92. doi: 10.1111/j.1523-1755.2004.00902.x.
5	Upregulation of vasopressin V2 and aquaporin 2 in the inner medullary collecting duct of cardiomyopathic hamsters is attenuated by enalapril treatment.Metabolism. 2002 Aug;51(8):970-5. doi: 10.1053/meta.2002.34015.
6	Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts.Hepatology. 2019 May;69(5):2107-2119. doi: 10.1002/hep.30499. Epub 2019 Mar 14.
7	Study of the association of -667 aquaporin-2 (AQP-2) A/G promoter polymorphism with the incidence and clinical course of chronic kidney disease in Korea.Ren Fail. 2007;29(6):693-8. doi: 10.1080/08860220701460079.
8	Obestatin Downregulating Aquaporin 2 Plasma Membrane Distribution Through a Short-Term Regulatory Effect.Am J Med Sci. 2019 Mar;357(3):247-254. doi: 10.1016/j.amjms.2018.12.010. Epub 2018 Dec 27.
9	Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus. Am J Hum Genet. 2001 Oct;69(4):738-48. doi: 10.1086/323643. Epub 2001 Aug 30.
10	Urinary Excretion of Kidney Aquaporins as Possible Diagnostic Biomarker of Diabetic Nephropathy.J Diabetes Res. 2017;2017:4360357. doi: 10.1155/2017/4360357. Epub 2017 Jan 26.
11	AQP2 is regulated by estradiol in human endometrium and is associated with spheroid attachment invitro.Mol Med Rep. 2019 Aug;20(2):1306-1312. doi: 10.3892/mmr.2019.10338. Epub 2019 Jun 5.
12	Identification of estrogen response element in the aquaporin-2 gene that mediates estrogen-induced cell migration and invasion in human endometrial carcinoma.J Clin Endocrinol Metab. 2011 Sep;96(9):E1399-408. doi: 10.1210/jc.2011-0426. Epub 2011 Jun 29.
13	The cardiovascular system in familial hypocalciuric hypercalcemia: a cross-sectional study on physiological effects of inactivating variants in the calcium-sensing receptor gene.Eur J Endocrinol. 2016 Oct;175(4):299-309. doi: 10.1530/EJE-16-0369. Epub 2016 Jul 14.
14	Trimethylamine-N-oxide (TMAO) increased aquaporin-2 expression in spontaneously hypertensive rats.Clin Exp Hypertens. 2019;41(4):312-322. doi: 10.1080/10641963.2018.1481420. Epub 2018 Jul 9.
15	Autophagy and renal epithelial transport: eat to survive.Kidney Int. 2017 May;91(5):1003-1005. doi: 10.1016/j.kint.2017.01.033.
16	Down-regulation of Na+ transporters and AQP2 is responsible for acyclovir-induced polyuria and hypophosphatemia.Kidney Int. 2004 Jan;65(1):175-83. doi: 10.1111/j.1523-1755.2004.00359.x.
17	Function of aquaporins in sepsis: a systematic review.Cell Biosci. 2018 Feb 9;8:10. doi: 10.1186/s13578-018-0211-9. eCollection 2018.
18	Gain-of-function mutations of the V2 vasopressin receptor in nephrogenic syndrome of inappropriate antidiuresis (NSIAD): a cell-based assay to assess constitutive water reabsorption.Pflugers Arch. 2019 Oct;471(10):1291-1304. doi: 10.1007/s00424-019-02307-x. Epub 2019 Sep 5.
19	Effects of cholecalciferol cholesterol emulsion on renal fibrosis and aquaporin 2 and 4 in mice with unilateral ureteral obstruction.Biomed Pharmacother. 2018 Jun;102:633-638. doi: 10.1016/j.biopha.2018.03.093. Epub 2018 Apr 5.
20	Expression pattern of aquaporins in patients with primary nephrotic syndrome with edema.Mol Med Rep. 2015 Oct;12(4):5625-32. doi: 10.3892/mmr.2015.4209. Epub 2015 Aug 11.
21	Inhibition of non-receptor tyrosine kinase Src induces phosphoserine 256-independent aquaporin-2 membrane accumulation.J Physiol. 2019 Mar;597(6):1627-1642. doi: 10.1113/JP277024. Epub 2018 Dec 21.
22	PNPLA3 Association with Alcoholic Liver Disease in a Cohort of Heavy Drinkers.Alcohol Alcohol. 2018 Jul 1;53(4):357-360. doi: 10.1093/alcalc/agy007.
23	Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018 Aug;50(8):1072-1080. doi: 10.1038/s41588-018-0157-1. Epub 2018 Jul 16.
24	Expression of aquaporins mRNAs in patients with otitis media.Acta Otolaryngol. 2018 Aug;138(8):701-707. doi: 10.1080/00016489.2018.1447685. Epub 2018 Apr 1.
25	Increased serum C-reactive protein and decreased urinary aquaporin 2 levels are predictive of the efficacy of tolvaptan in patients with liver cirrhosis.Hepatol Res. 2018 Feb;48(3):E311-E319. doi: 10.1111/hepr.12988. Epub 2017 Nov 3.
26	Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families.J Clin Endocrinol Metab. 2000 Apr;85(4):1703-10. doi: 10.1210/jcem.85.4.6507.
27	Hereditary Nephrogenic Diabetes Insipidus. 2000 Feb 12 [updated 2020 Feb 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
28	Arginine Vasopressin-Aquaporin-2 Pathway-Mediated Dehydration Effects of Electroacupuncture in Guinea Pig Model of AVP-Induced Eendolymphatic Hydrops.Chin J Integr Med. 2019 Oct;25(10):763-769. doi: 10.1007/s11655-017-2411-2. Epub 2018 Jan 15.
29	Urinary excretion of aquaporin-2 in pathological states of water metabolism.Ann Med. 2000 Mar;32(2):90-3. doi: 10.3109/07853890009011757.
30	Diabetes Insipidus.Adv Exp Med Biol. 2017;969:213-225. doi: 10.1007/978-94-024-1057-0_14.
31	Integrin linked kinase regulates the transcription of AQP2 by NFATC3.Biochim Biophys Acta Gene Regul Mech. 2017 Sep;1860(9):922-935. doi: 10.1016/j.bbagrm.2017.07.006. Epub 2017 Jul 20.
32	Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):263-76. doi: 10.1016/j.beem.2016.02.010. Epub 2016 Mar 2.
33	Mnire's Disease Pathophysiology: Endolymphatic Sac Immunohistochemical Study of Aquaporin-2, V2R Vasopressin Receptor, NKCC2, and TRPV4.Otolaryngol Head Neck Surg. 2018 Apr;158(4):721-728. doi: 10.1177/0194599818756829. Epub 2018 Feb 13.
34	Genetic predisposition and nongenetic risk factors of thiazolidinedione-related edema in patients with type 2 diabetes.Pharmacogenet Genomics. 2011 Dec;21(12):829-36. doi: 10.1097/FPC.0b013e32834bfff1.
35	A COMBINED OUTPATIENT AND INPATIENT OVERNIGHT WATER DEPRIVATION TEST IS EFFECTIVE AND SAFE IN DIAGNOSING PATIENTS WITH POLYURIA-POLYDIPSIA SYNDROME.Endocr Pract. 2018 Nov;24(11):963-972. doi: 10.4158/EP-2018-0238. Epub 2018 Aug 14.
36	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.
37	Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
38	Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla. Am J Physiol Renal Physiol. 2012 Sep 15;303(6):F900-5. doi: 10.1152/ajprenal.00547.2011. Epub 2012 Jul 11.
39	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.
40	DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
41	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.