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Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain

DC FieldValueLanguage
dc.contributor.author송종욱-
dc.date.accessioned2019-12-18T00:19:59Z-
dc.date.available2019-12-18T00:19:59Z-
dc.date.issued2018-
dc.identifier.issn0363-6135-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/172984-
dc.description.abstractSyndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1endo-/-) mice, the latter being a model of global endothelial dysfunction. We performed mass spectrometry analysis, which revealed that Synd4 was highly enriched in the secretome of renal microvascular endothelial cells obtained from Sirt1endo-/- mice upon stimulation with transforming growth factor-β1; notably, all detectable peptides were confined to the ectodomain of Synd4. Elevated Synd4 was due to enhanced NF-κB signaling in Sirt1endo-/- mice, while its shedding occurred as a result of oxidative stress in Sirt1 deficiency. Synd4 expression was significantly enhanced after unilateral ureteral obstruction compared with contralateral kidneys. Furthermore, hyperplasia of renal myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mice. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression levels of Synd4 in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain increased interstitial fibrosis. Moreover, the endothelial glycocalyx was reduced in Sirt1endo-/- mice, highlighting the induction of Synd4 occurring in parallel with the depletion of its intact form and accumulation of its ectodomain in Sirt1endo-/- mice. On the basis of our experimental results, we propose that it is the Synd4 ectodomain per se that is partially responsible for fibrosis in unilateral ureteral obstruction, especially when it is combined with endothelial dysfunction. NEW & NOTEWORTHY Our findings suggest that endothelial dysfunction induces the expression of syndecan-4 via activation of the NF-κB pathway. Furthermore, we show that syndecan-4 is shed to a greater amount because of increased oxidative stress in dysfunctional endothelial cells and that the release of the syndecan-4 ectodomain leads to tubulointerstitial fibrosis.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherAmerican Physiological Society-
dc.relation.isPartOfAMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESH• Animals-
dc.subject.MESHCells, Cultured-
dc.subject.MESHDisease Models, Animal-
dc.subject.MESHEndothelial Cells/metabolism*-
dc.subject.MESHEndothelial Cells/pathology-
dc.subject.MESHEndothelium, Vascular/metabolism*-
dc.subject.MESHEndothelium, Vascular/pathology-
dc.subject.MESHEndothelium, Vascular/physiopathology-
dc.subject.MESHFibrosis-
dc.subject.MESHGlycocalyx/metabolism-
dc.subject.MESHHyperplasia-
dc.subject.MESHKidney/blood supply*-
dc.subject.MESHKidney/metabolism-
dc.subject.MESHKidney/pathology-
dc.subject.MESHKidney Diseases/genetics-
dc.subject.MESHKidney Diseases/metabolism*-
dc.subject.MESHKidney Diseases/pathology-
dc.subject.MESHKidney Diseases/physiopathology-
dc.subject.MESHMice, Knockout-
dc.subject.MESHMicrovessels/metabolism*-
dc.subject.MESHMicrovessels/pathology-
dc.subject.MESHMicrovessels/physiopathology-
dc.subject.MESHMyofibroblasts/metabolism-
dc.subject.MESHMyofibroblasts/pathology-
dc.subject.MESHNF-kappa B/metabolism-
dc.subject.MESHOxidative Stress-
dc.subject.MESHProtein Domains-
dc.subject.MESHSignal Transduction-
dc.subject.MESHSirtuin 1/deficiency-
dc.subject.MESHSirtuin 1/genetics-
dc.subject.MESHSyndecan-4/metabolism*-
dc.subject.MESHUreteral Obstruction/metabolism-
dc.subject.MESHUreteral Obstruction/pathology-
dc.titleEndothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Anesthesiology and Pain Medicine (마취통증의학교실)-
dc.contributor.googleauthorMark Lipphardt-
dc.contributor.googleauthorJong W. Song-
dc.contributor.googleauthorBrian B. Ratliff-
dc.contributor.googleauthorHassan Dihazi-
dc.contributor.googleauthorGerhard A. Müller-
dc.contributor.googleauthorMichael S. Goligorsky-
dc.identifier.doi10.1152/ajpheart.00548.2017-
dc.contributor.localIdA02060-
dc.relation.journalcodeJ00105-
dc.identifier.eissn1522-1539-
dc.identifier.pmid29101181-
dc.subject.keywordendothelial glycocalyx-
dc.subject.keywordsirtuin 1-
dc.subject.keywordtubulointerstitial fibrosis-
dc.subject.keywordvascular endothelium-
dc.contributor.alternativeNameSong, Jong Wook-
dc.contributor.affiliatedAuthor송종욱-
dc.citation.volume314-
dc.citation.number3-
dc.citation.startPageH484-
dc.citation.endPageH496-
dc.identifier.bibliographicCitationAMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol.314(3) : H484-H496, 2018-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers

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