FGF7 peptide (FGF7p) mimetic mitigates bladder urothelial injury from cyclophosphamide. Issue 7 (7th April 2022) - Narla, Sridhar Tatarao
Abstract: Although full‐length fibroblast growth factor 7 (FGF7) blocks cyclophosphamide‐induced urothelial apoptosis in mice, limitations include high production costs because of its large size. We previously identified a small peptide derived from FGF2 that mitigated acute radiation syndrome as well as full‐length FGF2. Based on the sequence of the FGF2 peptide, we synthesized a corresponding 19 amino acid FGF7 peptide (FGF7p). Our objectives were to determine if systemic FGF7p triggered the downstream targets and protected against cyclophosphamide bladder injury similar to full‐length FGF7. We administered FGF7p or vehicle subcutaneously (SQ) to mice subjected to no injury or intraperitoneal (IP) cyclophosphamide and harvested bladders 1 day after injury. We then performed hematoxylin and eosin, TUNEL and immunofluorescence (IF) staining. In uninjured mice, a 20 mg/kg threshold FGF7p dose induced expression of phosphorylated (activated) FRS2α (pFRS2α), and pAKT in urothelium (consistent with cytoprotective effects of FGF7). We then gave FGF7p (20 mg/kg) or vehicle at 72 and 48 h prior to cyclophosphamide. One day after injury, TUNEL staining revealed many more apoptotic urothelial cells with vehicle treatment versus FGF7p treatment. IF for pAKT and readouts of two anti‐apoptotic AKT targets (BAD and mTORC1) revealed minimal staining with vehicle treatment, but strong urothelial expression for all markers with FGF7p treatment. In conclusion, FGF7p appears to block bladder urothelial apoptosis via AKT and its targets, similar to FGF7. FGF7p is much more inexpensive to make and has a longer shelf life and higher purity than FGF7. Abstract : We identified a small peptide derived from full‐length fibroblast growth factor 7 (FGF7) that we named FGF7 peptide (FGF7p). Similar to full‐length FGF7, systemic FGF7p drove widespread pFRS2alpha and pAKT staining and limited pERK expression and proliferation in uninjured mouse bladder urothelium. We also noted that pre‐treatment with FGF7p protected against cyclophosphamide‐induced bladder urothelial injury, likely via AKT targets known to be anti‐apoptotic, again similar to full length FGF7.