Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1IQMHV)

• DOT Name: Aquaporin-11 (AQP11)
• Synonyms: AQP-11
• Gene Name: AQP11
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Chronic kidney disease
  Diabetic kidney disease
  Non-insulin dependent diabetes
  Nephropathy
  Polycystic kidney disease
• UniProt ID: AQP11_HUMAN
• Pfam ID: PF00230
• Sequence:
  MSPLLGLRSELQDTCTSLGLMLSVVLLMGLARVVARQQLHRPVAHAFVLEFLATFQLCCC
  THELQLLSEQHPAHPTWTLTLVYFFSLVHGLTLVGTSSNPCGVMMQMMLGGMSPETGAVR
  LLAQLVSALCSRYCTSALWSLGLTQYHVSERSFACKNPIRVDLLKAVITEAVCSFLFHSA
  LLHFQEVRTKLRIHLLAALITFLVYAGGSLTGAVFNPALALSLHFMCFDEAFPQFFIVYW
  LAPSLGILLMILMFSFFLPWLHNNHTINKKE
• Function: Channel protein that facilitates the transport of water, glycerol and hydrogen peroxide across membrane of cell or organelles guaranteeing intracellular homeostasis in several organes like liver, kidney and brain. In situation of stress, participates in endoplasmic reticulum (ER) homeostasis by regulating redox homeostasis through the transport of hydrogen peroxide across the endoplasmic reticulum membrane thereby regulating the oxidative stress through the NADPH oxidase 2 pathway. Plays a role by maintaining an environment suitable for translation or protein foldings in the ER lumen namely by participating in the PKD1 glycosylation processing resulting in regulation of PKD1 membrane trafficking thereby preventing the accumulation of unfolding protein in ER. Plays a role in the proximal tubule function by regulating its endosomal acidification. May play a role in postnatal kidney development.
• Tissue Specificity: Detected in the sperm head and tail (at protein level) . Expressed in subcutaneous adipocytes . Expressed in testis, kidney and ejaculated spermatozoa .
• Reactome Pathway: Passive transport by Aquaporins (R-HSA-432047)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Genetic Variation	[1]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[2]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[2]
Polycystic kidney disease	DISWS3UY	No Known	Autosomal recessive	[3]

11 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 Aquaporin-11 (AQP11).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aquaporin-11 (AQP11).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aquaporin-11 (AQP11).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aquaporin-11 (AQP11).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Aquaporin-11 (AQP11).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aquaporin-11 (AQP11).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Aquaporin-11 (AQP11).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Aquaporin-11 (AQP11).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Aquaporin-11 (AQP11).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Aquaporin-11 (AQP11).	[10]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Aquaporin-11 (AQP11).	[13]

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 decreases the methylation of Aquaporin-11 (AQP11).	[14]

References

• [1] The distribution and function of aquaporins in the kidney: resolved and unresolved questions.Anat Sci Int. 2017 Mar;92(2):187-199. doi: 10.1007/s12565-016-0325-2. Epub 2016 Jan 21.
• [2] Aquaporin 11 rs2276415 variant and progression of chronic kidney disease.Nephrol Dial Transplant. 2019 Jun 1;34(6):970-973. doi: 10.1093/ndt/gfy219.
• [3] Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule. Mol Cell Biol. 2005 Sep;25(17):7770-9. doi: 10.1128/MCB.25.17.7770-7779.2005.
• [4] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] 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.