| Abstrakt: |
Keratinocyte growth factor (KGF) drives phosphorylated (activated) AKT (pAKT) in bladder urothelium which correlates with cytoprotection from cyclophosphamide. It was determined whether KGF modified AKT targets (BAD and mTORC1) that could block apoptosis, if AKT signaling is required for KGF cytoprotection and whether direct AKT activation can drive cytoprotection. Mice were given KGF and then cyclophosphamide (or sham injury) and pBAD (readout of BAD inhibition) or p-p70S6k (pS6, readout of mTORC1 signaling) were assessed. It was determined whether co-administration of KGF and an AKT inhibitor (AKTi) blocked urothelial cytoprotection and AKT and AKT target activation. It was also determined if an AKT agonist (AKTa) could prevent cyclophosphamide-induced urothelial apoptosis. Indeed, KGF induced pBAD urothelial staining and prevented cyclophosphamide-induced loss of urothelial pS6 staining (likely stabilizing mTORC1 activity). Moreover, co-administration of KGF and AKTiblocked KGF-driven urothelial cytoprotection from cyclophosphamide and prevented pAKT, pBAD and pS6 urothelial expression. Conversely, systemic AKTablocked cyclophosphamide-induced urothelial apoptosis and induced pAKT, pBAD and pS6, similar to KGF. Thus, the KGF-AKT signaling axis appears to phosphorylate (suppress) BAD and prevents cyclophosphamide-induced loss of mTOC1 signaling, both of which likely suppresses apoptosis. Also, AKT signaling is required for KGF-driven cytoprotection and direct AKT activation is sufficient to block apoptosis. Thus, AKT may be a therapeutic target to block urothelial apoptosis form cyclophosphamide. |
