Cyclosporine A - induced renal fibrosis: A role for epithelial-mesenchymal transition

Craig Slattery, Eric Campbell, Tara McMorrow, Michael P. Ryan*

*Corresponding author for this work

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

Cyclosporine A, which has been the foremost immunosuppressive agent since the early 1980's, significantly improves the success of organ transplantation. However, common complications of cyclosporine A therapy, such as severe renal tubulointerstitial fibrosis, limit the drug's clinical use. Although the exact mechanisms driving cyclosporine A-induced tubulointerstitial fibrosis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating human proximal tubular cells with cyclosporine A. Morphological changes were observed after cyclosporine A treatment, including cell elongation (with a large degree of detachment), cytoskeletal rearrangement, and junctional disruption. In addition, expression of the myofibroblast-specific marker α-smooth muscle actin was detected in treated cells. These observations are consistent with events described during EMT. Using Affymetrix gene microarrays, we identified 128 genes that were differentially regulated in renal tubular cells after cyclosporine A treatment, including known profibrotic factors, oncogenes, and transcriptional regulators. Cyclosporine A induced a dose-dependent increase in transforming growth factor-β secretion from proximal tubular cells. Subsequent functional studies revealed that protein kinase C-β isoforms play a key role in cyclosporine A-induced effects. These findings provide novel insights into cyclosporine A-induced renal fibrosis and the molecular mechanisms underlying EMT, events that may be relevant in other disease states.

Original languageEnglish
Pages (from-to)395-407
Number of pages13
JournalAmerican Journal of Pathology
Volume167
Issue number2
DOIs
Publication statusPublished - 01 Jan 2005
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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