TITLE

CELL BIOLOGY - IMMUNOLOGY - PATHOLOGY Sirolimus increases transforming growth factor-β1 expression and potentiates chronic cyclosporine nephrotoxicity

AUTHOR(S)
Shihab, Fuad S.; Bennett, William M.; Yi, Hong; Choi, Seung-Ok; Andoh, Takeshi F.
PUB. DATE
April 2004
SOURCE
Kidney International;Apr2004, Vol. 65 Issue 4, p1262
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Sirolimus increases transforming growth factor-β1 expression and potentiates chronic cyclosporine nephrotoxicity. Background. Sirolimus (SRL) is increasingly being used to decrease cyclosporine (CsA) exposure. SRL is not known to be nephrotoxic and has a mechanism of action distinct from CsA. We investigated the effect of combining CsA and SRL on renal structure and function and on transforming growth factor-β1 (TGF-β1) and extracellular matrix (ECM) proteins in a model of chronic CsA nephrotoxicity. Methods. Rats treated with vehicle, SRL 0.3 mg/kg/day, CsA 5 or 10 mg/kg/day, or CsA5+SRL were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to TGF-β1 mRNA and protein expressions, and mRNA expression of plasminogen activator inhibitor-1 (PAI-1) and ECM proteins biglycan and types I and IV collagen. Results. While SRL alone did not alter renal function and structure, it potentiated the nephrotoxic actions of CsA when used in combination with low-dose CsA5 and resulted in significant changes similar to high-dose CsA10. In addition, SRL alone increased TGF-β1 by 44% to 49% ( P < 0.05 vs. VH). When used in combination with low-dose CsA5, SRL potentiated TGF-β1 mRNA and protein by 121% and 176%, respectively ( P < 0.05 vs. VH and CsA5), to levels achieved with high-dose CsA10. The expression of the ECM proteins followed that of TGF-β1; a similar effect was observed with PAI-1, suggesting a decrease in ECM degradation. Conclusion. Because SRL augments nephrotoxicity, caution should be exercised when it is used in combination with CsA. More studies are needed to determine the long-term clinical impact of SRL on nephrotoxicity and allograft function.
ACCESSION #
12472462

 

Related Articles

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics