Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT21JD3P)

• DOT Name: Nephrin (NPHS1)
• Synonyms: Renal glomerulus-specific cell adhesion receptor
• Gene Name: NPHS1
• Related Disease:
  Congenital nephrotic syndrome, Finnish type
  Prostatitis
  Chronic kidney disease
  Chronic renal failure
  Colon cancer
  Colon carcinoma
  Exanthem
  Familial nephrotic syndrome
  High blood pressure
  Kidney failure
  Medium chain acyl-CoA dehydrogenase deficiency
  Membranous glomerulonephritis
  Nephropathy
  Nephrotic syndrome
  Non-insulin dependent diabetes
  Pre-eclampsia
  Steroid-resistant nephrotic syndrome
  Autosomal dominant medullary cystic kidney disease with or without hyperuricemia
  Glomerulonephritis
  Pierson syndrome
  Urinary tract infection
  Familial idiopathic steroid-resistant nephrotic syndrome
  Childhood kidney Wilms tumor
  Diphtheria
  End-stage renal disease
  Glaucoma/ocular hypertension
  Glomerulosclerosis
  Idiopathic nephrotic syndrome
  Macular corneal dystrophy
  Multiple sclerosis
  Nephrotic syndrome, type 2
  Nephrotic syndrome, type 3
  Type-1 diabetes
  Type-1/2 diabetes
  Wilms tumor
• UniProt ID: NPHN_HUMAN
• PDB ID: 4ZRT
• Pfam ID: PF08205 ; PF00041 ; PF07679 ; PF13927 ; PF07686
• Sequence:
  MALGTTLRASLLLLGLLTEGLAQLAIPASVPRGFWALPENLTVVEGASVELRCGVSTPGS
  AVQWAKDGLLLGPDPRIPGFPRYRLEGDPARGEFHLHIEACDLSDDAEYECQVGRSEMGP
  ELVSPRVILSILVPPKLLLLTPEAGTMVTWVAGQEYVVNCVSGDAKPAPDITILLSGQTI
  SDISANVNEGSQQKLFTVEATARVTPRSSDNRQLLVCEASSPALEAPIKASFTVNVLFPP
  GPPVIEWPGLDEGHVRAGQSLELPCVARGGNPLATLQWLKNGQPVSTAWGTEHTQAVARS
  VLVMTVRPEDHGAQLSCEAHNSVSAGTQEHGITLQVTFPPSAIIILGSASQTENKNVTLS
  CVSKSSRPRVLLRWWLGWRQLLPMEETVMDGLHGGHISMSNLTFLARREDNGLTLTCEAF
  SEAFTKETFKKSLILNVKYPAQKLWIEGPPEGQKLRAGTRVRLVCLAIGGNPEPSLMWYK
  DSRTVTESRLPQESRRVHLGSVEKSGSTFSRELVLVTGPSDNQAKFTCKAGQLSASTQLA
  VQFPPTNVTILANASALRPGDALNLTCVSVSSNPPVNLSWDKEGERLEGVAAPPRRAPFK
  GSAAARSVLLQVSSRDHGQRVTCRAHSAELRETVSSFYRLNVLYRPEFLGEQVLVVTAVE
  QGEALLPVSVSANPAPEAFNWTFRGYRLSPAGGPRHRILSSGALHLWNVTRADDGLYQLH
  CQNSEGTAEARLRLDVHYAPTIRALQDPTEVNVGGSVDIVCTVDANPILPGMFNWERLGE
  DEEDQSLDDMEKISRGPTGRLRIHHAKLAQAGAYQCIVDNGVAPPARRLLRLVVRFAPQV
  EHPTPLTKVAAAGDSTSSATLHCRARGVPNIVFTWTKNGVPLDLQDPRYTEHTYHQGGVH
  SSLLTIANVSAAQDYALFTCTATNALGSDQTNIQLVSISRPDPPSGLKVVSLTPHSVGLE
  WKPGFDGGLPQRFCIRYEALGTPGFHYVDVVPPQATTFTLTGLQPSTRYRVWLLASNALG
  DSGLADKGTQLPITTPGLHQPSGEPEDQLPTEPPSGPSGLPLLPVLFALGGLLLLSNASC
  VGGVLWQRRLRRLAEGISEKTEAGSEEDRVRNEYEESQWTGERDTQSSTVSTTEAEPYYR
  SLRDFSPQLPPTQEEVSYSRGFTGEDEDMAFPGHLYDEVERTYPPSGAWGPLYDEVQMGP
  WDLHWPEDTYQDPRGIYDQVAGDLDTLEPDSLPFELRGHLV
• Function: Seems to play a role in the development or function of the kidney glomerular filtration barrier. Regulates glomerular vascular permeability. May anchor the podocyte slit diaphragm to the actin cytoskeleton. Plays a role in skeletal muscle formation through regulation of myoblast fusion.
• Tissue Specificity: Specifically expressed in podocytes of kidney glomeruli.
• Reactome Pathway: Nephrin family interactions (R-HSA-373753)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital nephrotic syndrome, Finnish type	DIS8P7EH	Definitive	Autosomal recessive	[1]
Prostatitis	DISL8OGN	Definitive	Biomarker	[2]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[3]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Exanthem	DISAFOQN	Strong	Genetic Variation	[5]
Familial nephrotic syndrome	DISADF8G	Strong	Genetic Variation	[6]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[7]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[8]
Medium chain acyl-CoA dehydrogenase deficiency	DISB8C4K	Strong	Genetic Variation	[9]
Membranous glomerulonephritis	DISFSUKQ	Strong	Altered Expression	[10]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[11]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[12]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[13]
Pre-eclampsia	DISY7Q29	Strong	Altered Expression	[14]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Biomarker	[15]
Autosomal dominant medullary cystic kidney disease with or without hyperuricemia	DIS3PLLZ	moderate	Genetic Variation	[16]
Glomerulonephritis	DISPZIQ3	moderate	Biomarker	[17]
Pierson syndrome	DIS0DF3C	moderate	Genetic Variation	[18]
Urinary tract infection	DISMT6UV	moderate	Biomarker	[19]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[5]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Altered Expression	[20]
Diphtheria	DISZWM55	Limited	Biomarker	[21]
End-stage renal disease	DISXA7GG	Limited	Genetic Variation	[22]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[23]
Glomerulosclerosis	DISJF20Z	Limited	Biomarker	[24]
Idiopathic nephrotic syndrome	DISV4XYG	Limited	Genetic Variation	[24]
Macular corneal dystrophy	DISOLD0H	Limited	Altered Expression	[25]
Multiple sclerosis	DISB2WZI	Limited	Biomarker	[26]
Nephrotic syndrome, type 2	DISIRFO1	Limited	GermlineCausalMutation	[27]
Nephrotic syndrome, type 3	DISJKB7I	Limited	Biomarker	[28]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[29]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[29]
Wilms tumor	DISB6T16	Limited	Altered Expression	[20]

2 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 Nephrin (NPHS1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nephrin (NPHS1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nephrin (NPHS1).	[31]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nephrin (NPHS1).	[32]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Nephrin (NPHS1).	[33]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Nephrin (NPHS1).	[34]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Nephrin (NPHS1).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Nephrin (NPHS1).	[37]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Nephrin (NPHS1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nephrin (NPHS1).	[39]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Nephrin (NPHS1).	[40]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Nephrin (NPHS1).	[41]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Puromycin	DMDKLB5	Preclinical	Puromycin affects the localization of Nephrin (NPHS1).	[38]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Urovirulence determinants in Escherichia coli strains causing prostatitis.J Infect Dis. 1997 Aug;176(2):464-9. doi: 10.1086/514065.
• [3] Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.J Am Soc Nephrol. 2018 May;29(5):1513-1524. doi: 10.1681/ASN.2017101099. Epub 2018 Mar 15.
• [4] Colon cancer-associated B2 Escherichia coli colonize gut mucosa and promote cell proliferation.World J Gastroenterol. 2014 Jun 7;20(21):6560-72. doi: 10.3748/wjg.v20.i21.6560.
• [5] Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet. 2002 Feb 15;11(4):379-88. doi: 10.1093/hmg/11.4.379.
• [6] Urinary proteome signature of Renal Cysts and Diabetes syndrome in children.Sci Rep. 2019 Feb 18;9(1):2225. doi: 10.1038/s41598-019-38713-5.
• [7] Genetic polymorphism of NPHS1 modifies the clinical manifestations of Ig A nephropathy.Lab Invest. 2003 Aug;83(8):1193-200. doi: 10.1097/01.lab.0000080600.49276.31.
• [8] Genetic Interactions Between TRPC6 and NPHS1 Variants Affect Posttransplant Risk of Recurrent Focal Segmental Glomerulosclerosis.Am J Transplant. 2015 Dec;15(12):3229-38. doi: 10.1111/ajt.13378. Epub 2015 Jul 3.
• [9] Oligonucleotide ligation assay: applications to molecular diagnosis of inherited disorders.Scand J Clin Lab Invest. 2001 Apr;61(2):123-9. doi: 10.1080/00365510151097629.
• [10] Improvement of membranous nephropathy by inhibition of miR-193a to affect podocytosis via targeting WT1.J Cell Biochem. 2019 Mar;120(3):3438-3446. doi: 10.1002/jcb.27616. Epub 2018 Sep 22.
• [11] Coding variants in nephrin (NPHS1) and susceptibility to nephropathy in African Americans.Clin J Am Soc Nephrol. 2014 Aug 7;9(8):1434-40. doi: 10.2215/CJN.00290114. Epub 2014 Jun 19.
• [12] Detailed clinical manifestations at onset and prognosis of neonatal-onset Denys-Drash syndrome and congenital nephrotic syndrome of the Finnish type.Clin Exp Nephrol. 2019 Aug;23(8):1058-1065. doi: 10.1007/s10157-019-01732-7. Epub 2019 Apr 8.
• [13] Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats.J Diabetes. 2017 May;9(5):510-517. doi: 10.1111/1753-0407.12437. Epub 2016 Sep 12.
• [14] Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia.Nephrol Dial Transplant. 2007 Apr;22(4):1136-43. doi: 10.1093/ndt/gfl711. Epub 2007 Jan 25.
• [15] Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93.Pediatr Nephrol. 2018 Aug;33(8):1347-1363. doi: 10.1007/s00467-018-3950-2. Epub 2018 Jun 4.
• [16] Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology.Pediatr Nephrol. 2019 Sep;34(9):1493-1500. doi: 10.1007/s00467-018-4031-2. Epub 2018 Aug 11.
• [17] Testosterone and 17-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.Kidney Int. 2011 Feb;79(4):404-13. doi: 10.1038/ki.2010.398. Epub 2010 Oct 20.
• [18] Molecular pathology of nephrotic syndrome in childhood: a contemporary approach to diagnosis.Pediatr Dev Pathol. 2008 Jul-Aug;11(4):154-63. doi: 10.2350/07-11-0375.1.
• [19] Cytotoxic Necrotizing Factor-1 (CNF1) does not promote E. coli infection in a murine model of ascending pyelonephritis.BMC Microbiol. 2017 May 25;17(1):127. doi: 10.1186/s12866-017-1036-0.
• [20] Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo.Kidney Int. 2006 Oct;70(8):1456-62. doi: 10.1038/sj.ki.5001830. Epub 2006 Sep 6.
• [21] Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury.Kidney Int. 2017 Dec;92(6):1395-1403. doi: 10.1016/j.kint.2017.04.010. Epub 2017 Jul 12.
• [22] Post-Transplant Recurrence of Focal Segmental Glomerulosclerosis in a Child With Heterozygous Mutations in NPHS1 and NPHS2.Ther Apher Dial. 2016 Jun;20(3):312-7. doi: 10.1111/1744-9987.12443.
• [23] Whole exome sequencing identifies multiple diagnoses in congenital glaucoma with systemic anomalies.Clin Genet. 2016 Oct;90(4):378-82. doi: 10.1111/cge.12816. Epub 2016 Jul 12.
• [24] Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations.Clin J Am Soc Nephrol. 2009 Jun;4(6):1065-72. doi: 10.2215/CJN.03910808. Epub 2009 Apr 30.
• [25] Messenger RNA expression of B7-1 and NPHS1 in urinary sediment could be useful to differentiate between minimal-change disease and focal segmental glomerulosclerosis in adult patients.Nephrol Dial Transplant. 2011 Dec;26(12):3914-23. doi: 10.1093/ndt/gfr128. Epub 2011 Mar 17.
• [26] Cytokine secretion and nitric oxide production by mononuclear cells of patients with multiple sclerosis.J Neuroimmunol. 1997 Dec;80(1-2):76-86. doi: 10.1016/s0165-5728(97)00136-7.
• [27] Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.Kidney Int. 2009 Dec;76(12):1268-76. doi: 10.1038/ki.2009.381. Epub 2009 Oct 7.
• [28] Nephrin in experimental glomerular disease.Kidney Int. 2000 Oct;58(4):1461-8. doi: 10.1046/j.1523-1755.2000.00308.x.
• [29] Analysis of the intronic single nucleotide polymorphism rs#466452 of the nephrin gene in patients with diabetic nephropathy.Biol Res. 2009;42(2):189-98. Epub 2009 Aug 20.
• [30] 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.
• [31] Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy. Br J Pharmacol. 2018 Dec;175(23):4371-4385. doi: 10.1111/bph.14495. Epub 2018 Nov 6.
• [32] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [33] Simvastatin maintains steady patterns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes. Kidney Int. 2006 Jul;70(1):177-86. doi: 10.1038/sj.ki.5001515. Epub 2006 May 17.
• [34] Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-gamma agonist: molecular mechanism of the antiproteinuric effect of pioglitazone. J Am Soc Nephrol. 2006 Jun;17(6):1624-32. doi: 10.1681/ASN.2005090983. Epub 2006 May 10.
• [35] PPARalpha activation upregulates nephrin expression in human embryonic kidney epithelial cells and podocytes by a dual mechanism. Biochem Biophys Res Commun. 2005 Dec 30;338(4):1818-24. doi: 10.1016/j.bbrc.2005.10.158. Epub 2005 Nov 2.
• [36] 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.
• [37] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [38] Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. Am J Pathol. 2001 May;158(5):1723-31. doi: 10.1016/S0002-9440(10)64128-4.
• [39] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [40] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [41] Faster lipid -oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1 in human podocytes. J Biochem Mol Toxicol. 2021 Jul;35(7):e22797. doi: 10.1002/jbt.22797. Epub 2021 May 6.