title: Sirolimus toxicity and vascular endothelial growth factor release from islet and renal cell lines.
abstract: Presently, sirolimus (rapamycin) is used as both induction and maintenance immunosuppression in solid organ transplants, including whole pancreas and kidney, and islet transplantation. Sirolimus has been suggested to have deleterious effects on islet beta-cell and renal function. We investigated the effect of sirolimus on the viability of islets, podocytes, and renal tubular cells. Sirolimus reduced the viability of islets and HK-2 human proximal renal tubular cells in vitro. This toxic effect was associated with a reduction of vascular endothelial growth factor (VEGF) release by islets but not the proximal tubular cells. Sirolimus reduced both viability and VEGF production by murine beta-cells, and blockade of VEGF-164 was associated with a reduction in viability. Transfection of murine islets with adenoviral VEGF-165 improved islet viability. These data are consistent with the hypothesis that sirolimus is toxic to islets and beta-cells by blockade of VEGF-mediated survival pathways.
authors.affiliation: Academic Renal Unit, Paul O'Gorman Lifeline Centre, Clinical Science at North Bristol, Southmead Hospital, Westbury-on-Trym, Bristol, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Laugharne
authors.forename: Sarah
authors.initials: S
authors.lastname: Cross
authors.forename: Sarah
authors.initials: S
authors.lastname: Richards
authors.forename: Charlotte
authors.initials: C
authors.lastname: Dawson
authors.forename: Laura
authors.initials: L
authors.lastname: Ilchyshyn
authors.forename: Moin
authors.initials: M
authors.lastname: Saleem
authors.forename: Peter
authors.initials: P
authors.lastname: Mathieson
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D020123:Sirolimus