Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVP2WJM)

• DOT Name: Renalase (RNLS)
• Synonyms: EC 1.6.3.5; Monoamine oxidase-C; MAO-C
• Gene Name: RNLS
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Nephropathy
  Aortic valve stenosis
  Chronic kidney disease
  Chronic renal failure
  Coronary atherosclerosis
  Coronary heart disease
  Familial prostate carcinoma
  Glomerulonephritis
  Glomerulosclerosis
  Non-insulin dependent diabetes
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Type-1 diabetes
  Bipolar disorder
  End-stage renal disease
  Stroke
  Lung adenocarcinoma
  Pancreatic ductal carcinoma
• UniProt ID: RNLS_HUMAN
• PDB ID: 3QJ4
• EC Number: 1.6.3.5
• Pfam ID: PF01593 ; PF13450
• Sequence:
  MAQVLIVGAGMTGSLCAALLRRQTSGPLYLAVWDKAEDSGGRMTTACSPHNPQCTADLGA
  QYITCTPHYAKKHQRFYDELLAYGVLRPLSSPIEGMVMKEGDCNFVAPQGISSIIKHYLK
  ESGAEVYFRHRVTQINLRDDKWEVSKQTGSPEQFDLIVLTMPVPEILQLQGDITTLISEC
  QRQQLEAVSYSSRYALGLFYEAGTKIDVPWAGQYITSNPCIRFVSIDNKKRNIESSEIGP
  SLVIHTTVPFGVTYLEHSIEDVQELVFQQLENILPGLPQPIATKCQKWRHSQVTNAAANC
  PGQMTLHHKPFLACGGDGFTQSNFDGCITSALCVLEALKNYI
• Function: Catalyzes the oxidation of the less abundant 1,2-dihydro-beta-NAD(P) and 1,6-dihydro-beta-NAD(P) to form beta-NAD(P)(+). The enzyme hormone is secreted by the kidney, and circulates in blood and modulates cardiac function and systemic blood pressure. Lowers blood pressure in vivo by decreasing cardiac contractility and heart rate and preventing a compensatory increase in peripheral vascular tone, suggesting a causal link to the increased plasma catecholamine and heightened cardiovascular risk. High concentrations of catecholamines activate plasma renalase and promotes its secretion and synthesis.
• Tissue Specificity: Secreted into the blood by the kidney. Highly expressed in the kidney, expressed at lower level in heart, skeletal muscle and small intestine. Its plasma concentration is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects.
• Reactome Pathway: Nicotinamide salvaging (R-HSA-197264)
• BioCyc Pathway: MetaCyc:G66-32717-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Definitive	Biomarker	[1]
Congestive heart failure	DIS32MEA	Definitive	Biomarker	[1]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Aortic valve stenosis	DISW7AQ9	Strong	Genetic Variation	[3]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[4]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[5]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[6]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[6]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[7]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[8]
Glomerulosclerosis	DISJF20Z	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[7]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[10]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[11]
End-stage renal disease	DISXA7GG	moderate	Genetic Variation	[5]
Stroke	DISX6UHX	moderate	Genetic Variation	[12]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[13]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Renalase (RNLS).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Renalase (RNLS).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Renalase (RNLS).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Renalase (RNLS).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Renalase (RNLS).	[18]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Renalase (RNLS).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Renalase (RNLS).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Renalase (RNLS).	[21]

References

• [1] Renalase deficiency in heart failure model of rats--a potential mechanism underlying circulating norepinephrine accumulation.PLoS One. 2011 Jan 31;6(1):e14633. doi: 10.1371/journal.pone.0014633.
• [2] Renalase, a new renal hormone: its role in health and disease.Curr Opin Nephrol Hypertens. 2007 Jul;16(4):373-8. doi: 10.1097/MNH.0b013e3281bd8877.
• [3] Functional polymorphism of the renalase gene is associated with cardiac hypertrophy in female patients with aortic stenosis.PLoS One. 2017 Oct 24;12(10):e0186729. doi: 10.1371/journal.pone.0186729. eCollection 2017.
• [4] Renalase gene polymorphism and epinephrine level in chronic kidney disease.Appl Biochem Biotechnol. 2015 Feb;175(4):2309-17. doi: 10.1007/s12010-014-1433-x. Epub 2014 Dec 9.
• [5] Polymorphism of the renalase gene in end-stage renal disease patients affected by hypertension.Nephrol Dial Transplant. 2012 Nov;27(11):4162-6. doi: 10.1093/ndt/gfr293. Epub 2011 May 26.
• [6] Investigation of Renalase gene rs2576178 polymorphism in patients with coronary artery disease.Biosci Rep. 2018 Sep 13;38(5):BSR20180839. doi: 10.1042/BSR20180839. Print 2018 Oct 31.
• [7] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [8] Lisinopril protects against the adriamycin nephropathy and reverses the renalase reduction: potential role of renalase in adriamycin nephropathy.Kidney Blood Press Res. 2013;37(4-5):295-304. doi: 10.1159/000350157. Epub 2013 Sep 5.
• [9] Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls.Nat Genet. 2015 Jul;47(7):839-46. doi: 10.1038/ng.3330. Epub 2015 Jun 8.
• [10] Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.Nat Genet. 2015 Apr;47(4):381-6. doi: 10.1038/ng.3245. Epub 2015 Mar 9.
• [11] Genetics of long-term treatment outcome in bipolar disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2016 Feb 4;65:17-24. doi: 10.1016/j.pnpbp.2015.08.008. Epub 2015 Aug 20.
• [12] Renalase gene polymorphisms in patients with type 2 diabetes, hypertension and stroke.Neuromolecular Med. 2011 Dec;13(4):321-7. doi: 10.1007/s12017-011-8158-6. Epub 2011 Oct 2.
• [13] Genome-wide association study of familial lung cancer.Carcinogenesis. 2018 Sep 21;39(9):1135-1140. doi: 10.1093/carcin/bgy080.
• [14] Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer.Sci Rep. 2016 Mar 14;6:22996. doi: 10.1038/srep22996.
• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.