Sirolimus increases transforming growth factor-β1 expression and potentiates chronic cyclosporine nephrotoxicity

Fuad S. Shihab, William M. Bennett, Hong Yi, Seung Ok Choi, Takeshi F. Andoh

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1262-1271
Number of pages10
JournalKidney International
Volume65
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Keywords

  • Arteriolopathy
  • Biglycan
  • Chronic nephrotoxicity
  • Collagen
  • Cyclosporine
  • Extracellular matrix
  • Pharmacokinetics
  • Plasminogen activator inhibitor-1
  • Rapamycin
  • Rats
  • Sirolimus
  • Transforming growth factor-β1
  • Tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Nephrology

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