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Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells

Show simple item record El-Shewy H.M. Sohn M. Wilson P. Lee M.H. Hammad S.M. Luttrell L.M. Jaffa A.A.
dc.contributor.editor May-2012 2017-10-05T15:30:56Z 2017-10-05T15:30:56Z 2012
dc.identifier 10.1210/me.2011-1261
dc.identifier.issn 08888809
dc.description.abstract The pro-fibrotic connective tissue growth factor (CTGF) has been linked to the development and progression of diabetic vascular and renal disease.Werecently reported that low-density lipoproteins (LDL) induced expression of CTGF in aortic endothelial cells. However, the molecular mechanisms are not fully defined. Here, we have studied the mechanism by which LDL regulates CTGF expression in renal mesangial cells. In these cells, treatment with pertussis toxin abolished LDL-stimulated activation of ERK1-2 and c-Jun N-terminal kinase (JNK), indicating the involvement of heterotrimeric G proteins in LDL signaling. Treatment with LDL promoted activation and translocation of endogenous sphingosine kinase 1 (SK1) from the cytosol to the plasma membrane concomitant with production of sphingosine-1-phosphate (S1P). Pretreating cells with SK inhibitor, dimethylsphinogsine or downregulation of SK1 and SK2 revealed that LDL-dependent activation of ERK1-2 and JNK is mediated by SK1. Using a green fluorescent protein-tagged S1P1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that LDL induced S1P receptor activation. Pretreating cells with S1P1-S1P3 receptor antagonist VPC23019 significantly inhibited activation of ERK1-2 and JNK by LDL, suggesting that LDL elicits G protein-dependent activation of ERK1-2 and JNK by stimulating SK1-dependent transactivation of S1P receptors. Furthermore, S1P stimulation induced expression of CTGF in a dose-dependent manner that was markedly inhibited by blocking the ERK1-2 and JNK signaling pathways. LDL-induced CTGF expression was pertussis toxin sensitive and inhibited by dimethylsphinogsine down-regulation of SK1 and VPC23019 treatment. Our data suggest that SK1- dependent S1P receptor transactivation is upstream of ERK1-2 and JNK and that all three steps are required for LDL-regulated expression of CTGF in mesangial cells. © 2012 by The Endocrine Society.
dc.format.extent Pages: (833-845)
dc.language English
dc.publisher CHEVY CHASE
dc.relation.ispartof Publication Name: Molecular Endocrinology; Publication Year: 2012; Volume: 26; no. 5; Pages: (833-845);
dc.source Scopus
dc.title Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells
dc.type Article
dc.contributor.affiliation El-Shewy, H.M., Departments of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Sohn, M., Departments of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Wilson, P., Departments of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Lee, M.H., Departments of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Hammad, S.M., Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Luttrell, L.M., Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Jaffa, A.A., Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, United States, Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
dc.contributor.authorAddress Jaffa, A. A.; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Riad El-Solh Street, Beirut, Lebanon; email:
dc.contributor.authorCorporate University: American University of Beirut Medical Center; Faculty: Faculty of Medicine; Department: Biochemistry and Molecular Genetics;
dc.contributor.authorDepartment Biochemistry and Molecular Genetics
dc.contributor.faculty Faculty of Medicine
dc.contributor.authorInitials El-Shewy, HM
dc.contributor.authorInitials Sohn, M
dc.contributor.authorInitials Wilson, P
dc.contributor.authorInitials Lee, MH
dc.contributor.authorInitials Hammad, SM
dc.contributor.authorInitials Luttrell, LM
dc.contributor.authorInitials Jaffa, AA
dc.contributor.authorReprintAddress Jaffa, AA (reprint author), Amer Univ Beirut, Fac Med, Dept Biochem and Mol Genet, Riad El Solh St, Beirut, Lebanon.
dc.contributor.authorUniversity American University of Beirut Medical Center
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dc.description.citedCount 7
dc.description.citedTotWOSCount 8
dc.description.citedWOSCount 8
dc.format.extentCount 13
dc.identifier.coden MOENE
dc.identifier.pubmedID 22422617
dc.identifier.scopusID 84860333970
dc.publisher.address 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA
dc.relation.ispartOfISOAbbr Mol. Endocrinol.
dc.relation.ispartOfIssue 5
dc.relation.ispartofPubTitle Molecular Endocrinology
dc.relation.ispartofPubTitleAbbr Mol. Endocrinol.
dc.relation.ispartOfVolume 26
dc.source.ID WOS:000303864900012
dc.type.publication Journal
dc.subject.otherChemCAS mitogen activated protein kinase 1, 137632-08-7
dc.subject.otherChemCAS mitogen activated protein kinase 3, 137632-07-6
dc.subject.otherChemCAS n,n dimethylsphingosine, 122314-67-4
dc.subject.otherChemCAS pertussis toxin, 70323-44-3
dc.subject.otherChemCAS sphingosine 1 phosphate, 26993-30-6
dc.subject.otherChemCAS stress activated protein kinase, 155215-87-5
dc.subject.otherChemCAS Connective Tissue Growth Factor, 139568-91-5
dc.subject.otherChemCAS Lipoproteins, LDL
dc.subject.otherChemCAS Lysophospholipids
dc.subject.otherChemCAS Phosphotransferases (Alcohol Group Acceptor), 2.7.1.-
dc.subject.otherChemCAS Protein Isoforms
dc.subject.otherChemCAS RNA, Messenger
dc.subject.otherChemCAS RNA, Small Interfering
dc.subject.otherChemCAS Receptors, Lysosphingolipid
dc.subject.otherChemCAS Recombinant Fusion Proteins
dc.subject.otherChemCAS S1PR1 protein, human
dc.subject.otherChemCAS Sphingosine, 123-78-4
dc.subject.otherChemCAS sphingosine 1-phosphate, 26993-30-6
dc.subject.otherChemCAS sphingosine kinase, 2.7.1.-
dc.subject.otherIndex 2 amino 2 (3 octylphenylcarbamoyl)ethyl phosphate
dc.subject.otherIndex connective tissue growth factor
dc.subject.otherIndex green fluorescent protein
dc.subject.otherIndex guanine nucleotide binding protein
dc.subject.otherIndex low density lipoprotein
dc.subject.otherIndex mitogen activated protein kinase 1
dc.subject.otherIndex mitogen activated protein kinase 3
dc.subject.otherIndex n,n dimethylsphingosine
dc.subject.otherIndex pertussis toxin
dc.subject.otherIndex sphingosine 1 phosphate
dc.subject.otherIndex sphingosine 1 phosphate receptor
dc.subject.otherIndex sphingosine kinase 1
dc.subject.otherIndex sphingosine kinase 2
dc.subject.otherIndex stress activated protein kinase
dc.subject.otherIndex animal cell
dc.subject.otherIndex article
dc.subject.otherIndex controlled study
dc.subject.otherIndex diabetic angiopathy
dc.subject.otherIndex human
dc.subject.otherIndex human cell
dc.subject.otherIndex kidney injury
dc.subject.otherIndex lipid metabolism
dc.subject.otherIndex lipoprotein metabolism
dc.subject.otherIndex mesangium cell
dc.subject.otherIndex nonhuman
dc.subject.otherIndex priority journal
dc.subject.otherIndex rat
dc.subject.otherIndex Animals
dc.subject.otherIndex Cell Membrane
dc.subject.otherIndex Cells, Cultured
dc.subject.otherIndex Connective Tissue Growth Factor
dc.subject.otherIndex Diabetic Nephropathies
dc.subject.otherIndex Dyslipidemias
dc.subject.otherIndex Gene Silencing
dc.subject.otherIndex Humans
dc.subject.otherIndex Lipoproteins, LDL
dc.subject.otherIndex Lysophospholipids
dc.subject.otherIndex MAP Kinase Signaling System
dc.subject.otherIndex Mesangial Cells
dc.subject.otherIndex Phosphotransferases (Alcohol Group Acceptor)
dc.subject.otherIndex Protein Isoforms
dc.subject.otherIndex Protein Transport
dc.subject.otherIndex Rats
dc.subject.otherIndex Receptors, Lysosphingolipid
dc.subject.otherIndex Recombinant Fusion Proteins
dc.subject.otherIndex RNA, Messenger
dc.subject.otherIndex RNA, Small Interfering
dc.subject.otherIndex Sphingosine
dc.subject.otherIndex Transcriptional Activation
dc.subject.otherIndex Up-Regulation
dc.subject.otherKeywordPlus GLYCOSYLATION END-PRODUCTS
dc.subject.otherKeywordPlus PROTEIN-RELATED PROTEIN-2
dc.subject.otherKeywordPlus SMAD SIGNALING CASCADE
dc.subject.otherKeywordPlus P38 MAP KINASE
dc.subject.otherKeywordPlus ENDOTHELIAL-CELLS
dc.subject.otherKeywordPlus DIABETIC-NEPHROPATHY
dc.subject.otherKeywordPlus ATHEROSCLEROTIC LESIONS
dc.subject.otherKeywordPlus LYSOPHOSPHATIDIC ACID
dc.subject.otherKeywordPlus RENAL-DISEASE
dc.subject.otherWOS Endocrinology and Metabolism

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