title: Rapamycin is less fibrogenic than Cyclosporin A as demonstrated in a rat model of chronic allograft nephropathy.
abstract: BACKGROUND
  Cyclosporin A (CsA) is associated with significant chronic nephrotoxicity, which typically manifests as renal fibrosis. In contrast, rapamycin (RAPA) has been shown to inhibit fibrosis. This study sought to determine the effect of CsA and RAPA on the expression of connective tissue growth factor (CTGF) and E-cadherin in a rat kidney model of chronic allograft nephropathy.
  
  
  METHODS
  Left renal grafts from male Fisher (F344, RT1(1v1)) rats were orthotopically transplanted into Lewis (LEW, RT1(1)) rats. After transplantation, all recipients were given CsA 10 mg/kg(-1) d(-1) for 10 d and divided into three groups (n = 9/group): (1) vehicle, administered orally; (2) CsA, 6 mg/kg(-1) d(-1); (3) RAPA, 0.8 mg/kg(-1) d(-1). At 4, 8, and 12 wk posttransplantation, the kidney allografts were harvested and serum creatinine levels were measured. Connective tissue growth factor expression was determined using real-time polymerase chain reaction and Western blot. Kidney allografts sections also underwent hematoxylin-eosin and Masson trichrome staining, in addition to CTGF and E-cadherin immunostaining.
  
  
  RESULTS
  The serum creatinine levels were increased at 8 and 12 wk posttransplantation and were significantly lower in the RAPA group (P < 0.05). The Banff score also showed a significant decrease at 4, 8, and 12 wk (P < 0.05). CTGF messenger ribonucleic acid and protein levels were significantly lower in the RAPA group (P < 0.05), whereas E-cadherin expression was higher in the RAPA group at 4, 8, and 12 wk (P < 0.05). Masson's trichrome staining showed a significant decrease in collagen deposition at 8 and 12 wk after RAPA treatment.
  
  
  CONCLUSIONS
  RAPA can ameliorate fibrogenesis in kidney allografts by inhibiting epithelial-mesenchymal transition process, whereas CsA did not have this effect.
authors.affiliation: Department of Research and Education, Guizhou Province People's Hospital, Guiyang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Luo
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Sun
authors.forename: Guangheng
authors.initials: G
authors.lastname: Luo
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014184:Transplantation, Homologous
chemical_list: C526316:CCN2 protein, rat; D015820:Cadherins; D007166:Immunosuppressive Agents; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine; D003404:Creatinine; D020123:Sirolimus