Effect of cyclosporine and sirolimus on the expression of connective tissue growth factor in rat experimental chronic nephrotoxicity.
OBJECTIVE
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.


CONCLUSIONS
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.
Shihab
Fuad S
FS
Division of Nephrology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Fuad.Shihab@hsc.utah.edu
Bennett
William M
WM
Yi
Hong
H
Andoh
Takeshi F
TF
D000818:Animals; D002908:Chronic Disease; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015870:Gene Expression / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
C526316:CCN2 protein, rat; D004338:Drug Combinations; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine; D020123:Sirolimus