Possible mechanism by which rapamycin increases cyclosporine nephrotoxicity.
It is well known that the combination of cyclosporine A (CsA) with rapamycin produces serious nephrotoxicity. Herein we suggest a mechanism by which rapamycin increases CsA nephrotoxicity. Previously, we demonstrated that activation of Akt/protein kinase B protects against cyclosporine nephrotoxicity and prevents apoptosis. Recently, it has been shown that Akt phosphorylation activates mammalian target of rapamycin (m-TOR) and inhibits programmed cell death including apoptosis and autophagy. Akt is believed to be an importance factor for cell survival. In theory, blockade of the Akt pathway through inhibition of m-TOR may increase cyclosporine-induced apoptosis. We added cyclosporine and rapamycin to cultures of ER52K proximal renal tubule cells, leading to a significantly decreased survival rate. The nephrotoxicity was associated with increased apoptosis by cleavage of caspase-3 and decreased phosphorylation of m-TOR and AktSer473, findings that support this hypothesis. This nephrotoxic effect may explain the clinical finding that patients treated with rapamycin alone exhibited better renal function than those treated with concomitant cyclosporine therapy.
Cheng
C-H
CH
Department of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan.
Chang
H-R
HR
Chiang
C-W
CW
Shu
K-H
KH
Chou
M-C
MC
D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus