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Article: Elevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-β1 dependent and TGF-β1 independent pathways

TitleElevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-β1 dependent and TGF-β1 independent pathways
Authors
Issue Date2006
PublisherOxford University Press. The Journal's web site is located at http://ndt.oxfordjournals.org/
Citation
Nephrology Dialysis Transplantation, 2006, v. 21 n. 6, p. 1504-1513 How to Cite?
AbstractBackground. TGF-β1 bioactivation, consequent to the interaction of latent TGF-β1 with thrombospondin-1 (TSP-1), correlates with matrix accumulation in mesangial cells. Tubulointerstitial damage predicts poor renal survival. There is little data on TGF-β1 bioactivation and matrix synthesis in human proximal renal tubular epithelial cells under the influence of high glucose concentrations. This study thus investigates the role of TSP-1 in mediating elevated glucose-induction of TGF-β1 bioactivation and fibronectin (FN) synthesis in human proximal tubular epithelial cells. Methods. Human proximal renal tubular epithelial cells (HK-2 cells) were incubated with 5, 10, 20 or 30 mM D-glucose for up to 3 weeks either in the presence or absence of TSP-1 blocking peptide. In separate studies HK-2 cells were incubated with exogenous TSP-1 (0-10 ng/ml) or TGF-β1 (0-10 ng/ml) for 24 h. Cell proliferation was assessed by [ 3H]-thymidine incorporation. TGF-β1 transcript, secretion and bioactivity were investigated by quantitative real-time PCR, ELISA and the MLEC bioassay respectively. TSP-1 and FN synthesis were assessed by quantitative real-time PCR, ELISAs and Western blot analysis. Results. Elevated glucose concentrations increased TSP-1 synthesis, which was associated with reduced cell proliferation, increased TGF-β1 bioactivity, and stimulation of FN synthesis. The inclusion of TSP-1 blocking peptide to cells stimulated with elevated glucose concentration abrogated activation of TGF-β1 and induction of FN secretion. Exogenous TSP-1 increased bioactive TGF-β1 in HK-2 cells to initiate FN accumulation. Of interest is our observation that TSP-1 also increased matrix synthesis through a mechanism independent of TGF-β1. TGF-β1 in turn modulated TSP-1 synthesis, indicative of an autocrine loop between TSP-1 and TGF-β1. Conclusions. TSP-1 plays an important role in the induction of matrix synthesis by high glucose concentrations in human proximal renal tubular epithelial cells, through TGF-β1 dependent and TGF-β1 independent pathways. Pharmacological intervention targeting increased TSP-1 expression may interrupt the pathogenesis of diabetic nephropathy. © 2006 Oxford University Press.
Persistent Identifierhttp://hdl.handle.net/10722/162997
ISSN
2015 Impact Factor: 4.085
2015 SCImago Journal Rankings: 1.780
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYung, Sen_US
dc.contributor.authorLee, CYYen_US
dc.contributor.authorZhang, Qen_US
dc.contributor.authorLau, SKen_US
dc.contributor.authorTsang, RCWen_US
dc.contributor.authorChan, TMen_US
dc.date.accessioned2012-09-05T05:26:22Z-
dc.date.available2012-09-05T05:26:22Z-
dc.date.issued2006en_US
dc.identifier.citationNephrology Dialysis Transplantation, 2006, v. 21 n. 6, p. 1504-1513en_US
dc.identifier.issn0931-0509en_US
dc.identifier.urihttp://hdl.handle.net/10722/162997-
dc.description.abstractBackground. TGF-β1 bioactivation, consequent to the interaction of latent TGF-β1 with thrombospondin-1 (TSP-1), correlates with matrix accumulation in mesangial cells. Tubulointerstitial damage predicts poor renal survival. There is little data on TGF-β1 bioactivation and matrix synthesis in human proximal renal tubular epithelial cells under the influence of high glucose concentrations. This study thus investigates the role of TSP-1 in mediating elevated glucose-induction of TGF-β1 bioactivation and fibronectin (FN) synthesis in human proximal tubular epithelial cells. Methods. Human proximal renal tubular epithelial cells (HK-2 cells) were incubated with 5, 10, 20 or 30 mM D-glucose for up to 3 weeks either in the presence or absence of TSP-1 blocking peptide. In separate studies HK-2 cells were incubated with exogenous TSP-1 (0-10 ng/ml) or TGF-β1 (0-10 ng/ml) for 24 h. Cell proliferation was assessed by [ 3H]-thymidine incorporation. TGF-β1 transcript, secretion and bioactivity were investigated by quantitative real-time PCR, ELISA and the MLEC bioassay respectively. TSP-1 and FN synthesis were assessed by quantitative real-time PCR, ELISAs and Western blot analysis. Results. Elevated glucose concentrations increased TSP-1 synthesis, which was associated with reduced cell proliferation, increased TGF-β1 bioactivity, and stimulation of FN synthesis. The inclusion of TSP-1 blocking peptide to cells stimulated with elevated glucose concentration abrogated activation of TGF-β1 and induction of FN secretion. Exogenous TSP-1 increased bioactive TGF-β1 in HK-2 cells to initiate FN accumulation. Of interest is our observation that TSP-1 also increased matrix synthesis through a mechanism independent of TGF-β1. TGF-β1 in turn modulated TSP-1 synthesis, indicative of an autocrine loop between TSP-1 and TGF-β1. Conclusions. TSP-1 plays an important role in the induction of matrix synthesis by high glucose concentrations in human proximal renal tubular epithelial cells, through TGF-β1 dependent and TGF-β1 independent pathways. Pharmacological intervention targeting increased TSP-1 expression may interrupt the pathogenesis of diabetic nephropathy. © 2006 Oxford University Press.en_US
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://ndt.oxfordjournals.org/en_US
dc.relation.ispartofNephrology Dialysis Transplantationen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCell Proliferation - Drug Effectsen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshEpithelial Cells - Metabolismen_US
dc.subject.meshFibronectins - Biosynthesisen_US
dc.subject.meshGlucose - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshKidney Tubules, Proximal - Cytology - Metabolismen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshThrombospondin 1 - Drug Effects - Genetics - Physiologyen_US
dc.subject.meshTransforming Growth Factor Beta1 - Metabolismen_US
dc.subject.meshUp-Regulation - Drug Effectsen_US
dc.titleElevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-β1 dependent and TGF-β1 independent pathwaysen_US
dc.typeArticleen_US
dc.identifier.emailYung, S:ssyyung@hku.hken_US
dc.identifier.emailChan, TM:dtmchan@hku.hken_US
dc.identifier.authorityYung, S=rp00455en_US
dc.identifier.authorityChan, TM=rp00394en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1093/ndt/gfl017en_US
dc.identifier.pmid16495290-
dc.identifier.scopuseid_2-s2.0-33745995085en_US
dc.identifier.hkuros117901-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33745995085&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume21en_US
dc.identifier.issue6en_US
dc.identifier.spage1504en_US
dc.identifier.epage1513en_US
dc.identifier.isiWOS:000238538100009-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridYung, S=22636568800en_US
dc.identifier.scopusauthoridLee, CYY=49763466000en_US
dc.identifier.scopusauthoridZhang, Q=37021921200en_US
dc.identifier.scopusauthoridLau, SK=49763231400en_US
dc.identifier.scopusauthoridTsang, RCW=36808555100en_US
dc.identifier.scopusauthoridChan, TM=7402687700en_US
dc.identifier.citeulike683027-

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