AKT signaling downstream of KGF is necessary and sufficient for blocking cyclophosphamide bladder injury

Am J Pathol. 2022 Jan 18:S0002-9440(22)00005-0. doi: 10.1016/j.ajpath.2022.01.004. Online ahead of print.ABSTRACTKeratinocyte 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 AKTi blocked KGF-driven urothelial cytoprotection from cyclophosphamide and prevented pAKT, pBAD and pS6 urothelial expression. Conversely, systemic AKTa blocked 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 l...

Source: The American Journal of Pathology - January 22, 2022 Category: Pathology Authors: Sridhar Tatarao Narla Daniel Scott Bushnell Joanne Lindsey Duara Carlton Matthew Bates Source Type: research