title: Sirolimus reduces vasculopathy but exacerbates proteinuria in association with inhibition of VEGF and VEGFR in a rat kidney model of chronic allograft dysfunction.
abstract: BACKGROUND
  Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology.
  
  
  METHODS
  Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed.
  
  
  RESULTS
  Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells.
  
  
  CONCLUSIONS
  Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.
authors.affiliation: Collaborative transplantation laboratory, Sydney Medical School and Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Hung T
authors.initials: HT
authors.lastname: Ko
authors.forename: Jian L
authors.initials: JL
authors.lastname: Yin
authors.forename: Kate
authors.initials: K
authors.lastname: Wyburn
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
authors.forename: Josette M
authors.initials: JM
authors.lastname: Eris
authors.forename: Brett D
authors.initials: BD
authors.lastname: Hambly
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chadban
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011507:Proteinuria / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D016572:Cyclosporine; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus