Tags

Type your tag names separated by a space and hit enter

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.
Nephrol Dial Transplant. 2006 Jun; 21(6):1504-13.ND

Abstract

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.

Authors+Show Affiliations

Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong SAR, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16495290

Citation

Yung, Susan, et al. "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." Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, vol. 21, no. 6, 2006, pp. 1504-13.
Yung S, Lee CY, Zhang Q, et al. 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. Nephrol Dial Transplant. 2006;21(6):1504-13.
Yung, S., Lee, C. Y., Zhang, Q., Lau, S. K., Tsang, R. C., & Chan, T. M. (2006). 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. Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, 21(6), 1504-13.
Yung S, et al. 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. Nephrol Dial Transplant. 2006;21(6):1504-13. PubMed PMID: 16495290.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Yung,Susan, AU - Lee,Candice Y Y, AU - Zhang,Qing, AU - Lau,Shuk Kei, AU - Tsang,Ryan C W, AU - Chan,Tak Mao, Y1 - 2006/02/22/ PY - 2006/2/24/pubmed PY - 2006/12/9/medline PY - 2006/2/24/entrez SP - 1504 EP - 13 JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JO - Nephrol. Dial. Transplant. VL - 21 IS - 6 N2 - 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. SN - 0931-0509 UR - https://www.unboundmedicine.com/medline/citation/16495290/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_ L2 - https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfl017 DB - PRIME DP - Unbound Medicine ER -