RT info:eu-repo/semantics/article
T1 Título: Inhibition of the mTOR pathway: a new mechanism of ß-cell toxicity induced by Tacrolimus.
Revista: American Journal of Transplantation (2019) 19(12):3240-3249 
Autores: Rodriguez-Rodriguez, A.E.; Donate-Correa, J.; Rovira, J.; Cuesto, G.; Luis-Ravelo, D.; Fernandes M..X.; Acevedo-Arozena, A.; Diekmann, F.; Acebes, A.; Torres, A.; Porrini, E.
A1 Acebes Vindel, Ángel José
A1 Rodríguez Rodríguez, Ana Elena
A1 Donate Correa, Javier
A1 Rovira, Jordi
A1 Cuesto, Germán
A1 Luis Ravelo, Diego
A1 Fernandes, Miguel X
A1 Acevedo Arozarena, Abraham
A1 Diekmann, Fritz
A1 Torres, Armando
A1 Porrini, Esteban
A2 Ciencias Médicas Básicas
K1 Animal models
K1 Basic (laboratory) research/science
K1 Cellular biology
K1 Diabetes
K1 Immunosuppressant ‐ calcineurin inhibitor
K1 Immunosuppressant ‐ mechanistic target of
rapamycin (mTOR)
K1 Kidney transplantation/nephrology
K1 Molecular biology
K1 Murine
K1 New onset/posttransplant
K1 Tacrolimus
AB The mechanisms of tacrolimus‐induced β cell toxicity are unknown. Tacrolimus (TAC) and Rapamycin (Rapa) both bind to FK506‐binding protein 12 (FKBP12). Also, both molecular structures are similar. Because of this similarity, we hypothesized that TAC can also inhibit the mTOR signalling, constituting a possible mechanism of β cell toxicity. Thus, we studied the effect of TAC and Rapa over the mTOR pathway, v‐maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and insulin secretion andcontent in INS‐1 β cells treated with or without glucose and palmitate and in isletsfrom lean or obese rats. TAC and Rapa inhibited the mTOR pathway as reflected bylower levels of phospho‐mTOR, phospo-p70S6K, and phospo‐S6. The effect of Rapawas larger than TAC. Both drugs reduced the levels of MafA, insulin secretion, and content although these effects were larger with TAC. The changes on MafA and insulin metabolism were observed in cells on glucose and palmitate, in obese animals, and were absent in cells on maintenance medium or in lean animals. In silico docking and immunoprecipitation experiments confirmed that TAC can form a stable noncovalentinteraction with FKBP12‐mTOR. Thus, the mTOR inhibition may be a mechanism contributing to the diabetogenic effect of TAC.
PB The American Society of Transplantation and the American Society of Transplant Surgeons
YR 2019
FD 2019
LK http://riull.ull.es/xmlui/handle/915/35823
UL http://riull.ull.es/xmlui/handle/915/35823
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 21-dic-2024