title: Epithelial phenotypic changes detect cyclosporine in vivo nephrotoxicity at a reversible stage.
abstract: BACKGROUND
  A widely used immunosuppressant, cyclosporine A (CsA), conveys long-term nephrotoxicity in some patients. However, no specific marker is presently available. In both native and transplanted human kidneys, epithelial phenotypic changes (EPCs) suggestive of epithelial to mesenchymal transition (EMT) are expressed in various diseases and are prognostic with respect to progression of interstitial fibrosis. We hypothesized that CsA is able to trigger these EPCs in tubular cells in vivo.
  
  
  METHODS
  We studied the kinetics of the EMT markers β-catenin, snail, vimentin, collagen III, and HSP47 at the messenger RNA and protein levels in the kidneys from rats injected with 15 mg/kg/day of CsA or its vehicle. We investigated several therapeutic strategies available to block EMT in this model.
  
  
  RESULTS
  By 2 weeks, CsA had induced histological changes (tubular dilatation and vacuoles) and overexpression of EMT-related genes. This up-regulation of the EMT program was associated with tubular, not interstitial, overexpression of mesenchymal markers. Angiotensin II and endothelin receptor antagonists failed to prevent this CsA-induced EMT. Interestingly, CsA withdrawal led to the gradual regression of histological lesions and EMT, demonstrating that it not only prevents progression but also allows healing of renal injury.
  
  
  CONCLUSIONS
  Our study suggests that detecting EPC could help to identify ongoing renal CsA-induced toxicity at an early and reversible stage.
authors: INSERM U702, Paris, France. galichon@orange.fr
authors: Pierre
authors: P
authors: Galichon
authors: Nathalie
authors: N
authors: Vittoz
authors: Yi-Chun
authors: YC
authors: Xu-Dubois
authors: Emilie
authors: E
authors: Cornaire
authors: Sophie
authors: S
authors: Vandermeersch
authors: Laurent
authors: L
authors: Mesnard
authors: Alexandre
authors: A
authors: Hertig
authors: Eric
authors: E
authors: Rondeau
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D050958:HSP47 Heat-Shock Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D023421:Models, Animal; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024061:Collagen Type III; D050958:HSP47 Heat-Shock Proteins; D007166:Immunosuppressive Agents; C494662:Serpinh1 protein, rat; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D051176:beta Catenin; D000804:Angiotensin II; D016572:Cyclosporine