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Published on: July 3, 2013
Effect of cyclosporine and sirolimus on the expression of connective tissue growth factor in rat experimental chronic
Fuad S Shihab1, William M Bennett, Hong Yi
1Division of Nephrology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Fuad.Shihab@hsc.utah.edu
Background/Aims:
Connective tissue growth factor (CTGF) is a pro-fibrotic growth factor that acts downstream of transforming growth factor (TGF)-beta. However, CTGF regulation remains unknown. We tried to determine the effect of two commonly used immunosuppressants, cyclosporine (CsA) and sirolimus (SRL), on CTGF expression in a model of chronic nephrotoxicity.
Methods:
Adult Sprague-Dawley rats kept on a low-salt diet were treated daily for 4 weeks with vehicle (VH), SRL (0.3 mg/kg), CsA5 (5 mg/kg), CsA10 (10 mg/kg) or both CsA5 and SRL. CTGF and TGF-beta1 expressions were evaluated by Northern blot. Functional and histologic parameters in addition to number of apoptotic cells were determined.
Results:
At 28 days, both CsA doses were capable of inhibiting CTGF mRNA expression to levels similar to control. On the other hand, SRL increased CTGF expression by 3.5-fold. However, addition of CsA to SRL completely reversed that trend and returned levels to control. The results were different for TGF-beta1, which was increased by both CsA and SRL and to a greater extent by the drug combination.
Conclusion:
Unlike TGF-beta, CTGF does not seem to play an important role in CsA-induced chronic nephrotoxicity. In addition, calcineurin-dependent pathways are likely involved in CTGF regulation.
Insights
Cyclosporine (CsA) inhibits connective tissue growth factor (CTGF) expression, while sirolimus (SRL) increases it. CsA counteracts SRL's effect on CTGF in a chronic nephrotoxicity model.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Connective tissue growth factor (CTGF) is a key mediator in fibrotic processes.
- CTGF acts downstream of transforming growth factor (TGF)-beta, but its regulation is not fully understood.
- Understanding CTGF regulation is crucial for managing fibrotic diseases, including chronic nephrotoxicity.
Purpose of the Study:
- To investigate the impact of immunosuppressants cyclosporine (CsA) and sirolimus (SRL) on CTGF expression.
- To determine the role of CTGF in CsA-induced chronic nephrotoxicity.
- To explore the relationship between CTGF and TGF-beta1 in this model.
Main Methods:
- Adult Sprague-Dawley rats were administered vehicle, SRL, CsA (two doses), or a combination of CsA and SRL for 4 weeks.
- CTGF and TGF-beta1 mRNA expression were quantified using Northern blot.
- Renal function, histology, and apoptosis were assessed.
Main Results:
- Both doses of CsA significantly inhibited CTGF mRNA expression.
- SRL alone increased CTGF expression by 3.5-fold.
- CsA reversed the SRL-induced increase in CTGF, returning levels to control; however, both agents and their combination elevated TGF-beta1 levels.
Conclusions:
- CTGF appears not to be a major factor in CsA-induced chronic nephrotoxicity.
- Calcineurin-dependent pathways are likely involved in the regulation of CTGF.
- The differential effects of CsA and SRL on CTGF and TGF-beta1 highlight distinct mechanisms of action.