| Elevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-beta1 dependent and TGF-beta1 independent pathways. | |
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MedLine Citation:
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PMID: 16495290 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: TGF-beta1 bioactivation, consequent to the interaction of latent TGF-beta1 with thrombospondin-1 (TSP-1), correlates with matrix accumulation in mesangial cells. Tubulointerstitial damage predicts poor renal survival. There is little data on TGF-beta1 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-beta1 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-beta1 (0-10 ng/ml) for 24 h. Cell proliferation was assessed by [(3)H]-thymidine incorporation. TGF-beta1 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-beta1 bioactivity, and stimulation of FN synthesis. The inclusion of TSP-1 blocking peptide to cells stimulated with elevated glucose concentration abrogated activation of TGF-beta1 and induction of FN secretion. Exogenous TSP-1 increased bioactive TGF-beta1 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-beta1. TGF-beta1 in turn modulated TSP-1 synthesis, indicative of an autocrine loop between TSP-1 and TGF-beta1. 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-beta1 dependent and TGF-beta1 independent pathways. Pharmacological intervention targeting increased TSP-1 expression may interrupt the pathogenesis of diabetic nephropathy. |
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Authors:
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Susan Yung; Candice Y Y Lee; Qing Zhang; Shuk Kei Lau; Ryan C W Tsang; Tak Mao Chan |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-02-22 |
Journal Detail:
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Title: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Volume: 21 ISSN: 0931-0509 ISO Abbreviation: Nephrol. Dial. Transplant. Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-05-22 Completed Date: 2006-11-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8706402 Medline TA: Nephrol Dial Transplant Country: England |
Other Details:
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Languages: eng Pagination: 1504-13 Citation Subset: IM |
Affiliation:
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Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong SAR, China. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Line Cell Proliferation / drug effects Dose-Response Relationship, Drug Epithelial Cells / metabolism* Fibronectins / biosynthesis* Glucose / pharmacology Humans Kidney Tubules, Proximal / cytology*, metabolism Signal Transduction* Thrombospondin 1 / drug effects, genetics*, physiology* Transforming Growth Factor beta1 / metabolism* Up-Regulation / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Fibronectins; 0/Thrombospondin 1; 0/Transforming Growth Factor beta1; 50-99-7/Glucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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