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Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis
S Gupta1, M R Clarkson, J Duggan
1Department of Medicine and Therapeutics, Mater Misericordiae Hospital, University College Dublin, Dublin, Ireland.
Abstract:
Transforming growth factor beta (TGF-beta) is a pivotal driver of glomerulosclerosis and tubulointerstitial fibrosis in renal diseases. Because TGF-beta also plays important anti-inflammatory and antiproliferative roles in mammalian systems, there has been a recent drive to elucidate downstream mediators of TGF-beta's pro-fibrotic effects with the ultimate goal of developing new anti-fibrotic strategies for treatment of chronic diseases. Connective tissue growth factor (CTGF) belongs to the CCN family of immediate early response genes. Several lines of evidence suggest that CTGF is an important pro-fibrotic molecule in renal disease and that CTGF contributes to TGF-beta bioactivity in this setting. CTGF expression is increased in the glomeruli and tubulointerstium in a variety of renal disease in association with scarring and sclerosis of renal parenchyma. In model systems in vitro, mesangial cell CTGF expression is induced by high extracellular glucose, cyclic mechanical strain and TGF-beta. Recombinant human CTGF augments the production of fibronectin and type IV collagen by mesangial cells and the effects of high glucose on mesangial cell CTGF expression and matrix production are attenuated, in part, by anti-TGF-beta antibody. In aggregate, these observations identify CTGF as an attractive therapeutic target in fibrotic renal diseases.
Insights
Transforming growth factor beta (TGF-beta) drives kidney fibrosis. Connective tissue growth factor (CTGF) is a key mediator of TGF-beta
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor beta (TGF-beta) is a key driver of glomerulosclerosis and renal fibrosis.
- Understanding TGF-beta's pro-fibrotic pathways is crucial for developing anti-fibrotic therapies.
- Connective tissue growth factor (CTGF) is implicated in mediating TGF-beta's fibrotic effects in the kidney.
Purpose of the Study:
- To investigate the role of CTGF as a downstream mediator of TGF-beta's pro-fibrotic effects in renal disease.
- To explore CTGF as a potential therapeutic target for fibrotic kidney diseases.
Main Methods:
- Review of evidence linking CTGF to renal fibrosis and TGF-beta bioactivity.
- Analysis of CTGF expression in diseased renal tissues.
- In vitro studies using mesangial cells to assess CTGF induction and matrix production under various stimuli (high glucose, mechanical strain, TGF-beta).
Main Results:
- CTGF expression is elevated in various renal diseases, correlating with renal scarring.
- Mesangial cell CTGF expression is induced by high glucose, mechanical strain, and TGF-beta.
- Recombinant CTGF enhances fibronectin and type IV collagen production by mesangial cells.
- Anti-TGF-beta antibodies partially reduce high glucose-induced CTGF expression and matrix production.
Conclusions:
- CTGF is a significant pro-fibrotic molecule in renal disease and contributes to TGF-beta's bioactivity.
- CTGF represents a promising therapeutic target for mitigating renal fibrosis.