Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2NRMJP)

• DOT Name: Type-1 angiotensin II receptor (AGTR1)
• Synonyms: AT1AR; AT1BR; Angiotensin II type-1 receptor; AT1 receptor
• Gene Name: AGTR1
• Related Disease:
  Renal tubular dysgenesis of genetic origin
  Essential hypertension, genetic
• UniProt ID: AGTR1_HUMAN
• PDB ID: 4YAY; 4ZUD; 6DO1; 6OS0; 6OS1; 6OS2
• Pfam ID: PF00001
• Sequence:
  MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFVVGIFGNSLVVIVIYFYMKLK
  TVASVFLLNLALADLCFLLTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASVFLLT
  CLSIDRYLAIVHPMKSRLRRTMLVAKVTCIIIWLLAGLASLPAIIHRNVFFIENTNITVC
  AFHYESQNSTLPIGLGLTKNILGFLFPFLIILTSYTLIWKALKKAYEIQKNKPRNDDIFK
  IIMAIVLFFFFSWIPHQIFTFLDVLIQLGIIRDCRIADIVDTAMPITICIAYFNNCLNPL
  FYGFLGKKFKRYFLQLLKYIPPKAKSHSNLSTKMSTLSYRPSDNVSSSTKKPAPCFEVE
• Function: Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney. The activated receptor in turn couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C ; (Microbial infection) During SARS coronavirus-2/SARS-CoV-2 infection, it is able to recognize and internalize the complex formed by secreted ACE2 and SARS-CoV-2 spike protein through DNM2/dynamin 2-dependent endocytosis.
• Tissue Specificity: Liver, lung, adrenal and adrenocortical adenomas.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Renin-angiotensin system (hsa04614)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Cushing syndrome (hsa04934)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Renal tubular dysgenesis of genetic origin	DISIP4Y5	Strong	Autosomal recessive	[1]
Essential hypertension, genetic	DISIVD4P	No Known	Unknown	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Perindopril	DMOPZDT	Approved	Type-1 angiotensin II receptor (AGTR1) affects the response to substance of Perindopril.	[21]
Nitrendipine	DM21C09	Approved	Type-1 angiotensin II receptor (AGTR1) affects the response to substance of Nitrendipine.	[21]
Irbesartan	DMTP1DC	Investigative	Type-1 angiotensin II receptor (AGTR1) affects the response to substance of Irbesartan.	[22]

18 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 Type-1 angiotensin II receptor (AGTR1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Type-1 angiotensin II receptor (AGTR1).	[10]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[11]
Estriol	DMOEM2I	Approved	Estriol decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[7]
Fructose	DM43AN2	Approved	Fructose increases the expression of Type-1 angiotensin II receptor (AGTR1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Type-1 angiotensin II receptor (AGTR1).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Type-1 angiotensin II receptor (AGTR1).	[16]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Type-1 angiotensin II receptor (AGTR1).	[17]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Type-1 angiotensin II receptor (AGTR1).	[12]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Type-1 angiotensin II receptor (AGTR1).	[18]
PAF	DMRZAQW	Investigative	PAF increases the expression of Type-1 angiotensin II receptor (AGTR1).	[19]
Erythropoietin	DM3R8YL	Investigative	Erythropoietin decreases the activity of Type-1 angiotensin II receptor (AGTR1).	[20]

2 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 increases the methylation of Type-1 angiotensin II receptor (AGTR1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Type-1 angiotensin II receptor (AGTR1).	[14]

References

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• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] The combination of EGCG with warfarin reduces deep vein thrombosis in rabbits through modulating HIF-1 and VEGF via the PI3K/AKT and ERK1/2 signaling pathways. Chin J Nat Med. 2022 Sep;20(9):679-690. doi: 10.1016/S1875-5364(22)60172-9.
• [11] Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin. J Cardiovasc Pharmacol. 2007 May;49(5):299-305. doi: 10.1097/FJC.0b013e31803d35ce.
• [12] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [13] 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.
• [14] 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.
• [15] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
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• [17] Paraquat increases connective tissue growth factor and collagen expression via angiotensin signaling pathway in human lung fibroblasts. Toxicol In Vitro. 2010 Apr;24(3):803-8. doi: 10.1016/j.tiv.2009.12.015. Epub 2009 Dec 24.
• [18] Dibutyl phthalate induces epithelial-mesenchymal transition of renal tubular epithelial cells via the Ang II/AMPK2/Cx43 signaling pathway. Toxicology. 2023 Aug 1;494:153584. doi: 10.1016/j.tox.2023.153584. Epub 2023 Jun 24.
• [19] Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophagesImplications in atherosclerosis. Atherosclerosis. 2006 Oct;188(2):433-43.
• [20] AT1 receptor blockade and the sympathoadrenal response to insulin-induced hypoglycemia in humans. Am J Physiol. 1997 Mar;272(3 Pt 1):E415-21. doi: 10.1152/ajpendo.1997.272.3.E415.
• [21] Influence of the angiotensin II type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension. 1996 Dec;28(6):1081-4. doi: 10.1161/01.hyp.28.6.1081.
• [22] Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. J Hypertens. 2002 Apr;20(4):657-63. doi: 10.1097/00004872-200204000-00023.