Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide
Abstract We previously identified a peptide derived from human fibroblast growth factor 7 (FGF7p) that blocks urothelial apoptosis similar to full‐length FGF7, although effects of FGF7p on urothelial repair are unknown. Also, while urothelial AKT activation downstream of FGF7p correlated with the an...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.15358 |
| _version_ | 1797392819016433664 |
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| author | Sridhar Tatarao Narla Lori Rice David Ostrov Daniel Scott Bushnell Joanne Lindsey Duara Carlton Matthew Bates |
| author_facet | Sridhar Tatarao Narla Lori Rice David Ostrov Daniel Scott Bushnell Joanne Lindsey Duara Carlton Matthew Bates |
| author_sort | Sridhar Tatarao Narla |
| collection | DOAJ |
| description | Abstract We previously identified a peptide derived from human fibroblast growth factor 7 (FGF7p) that blocks urothelial apoptosis similar to full‐length FGF7, although effects of FGF7p on urothelial repair are unknown. Also, while urothelial AKT activation downstream of FGF7p correlated with the anti‐apoptotic effects, we have not directly interrogated the role of AKT in mediating the cytoprotection. Our goal was to assess effects of FGF7p on urothelial repair and the role of AKT signaling in mediating the cytoprotective effects of FGF7p. We performed hematoxylin and eosin (H&E), TUNEL, and/or immunofluorescence (IF) staining for various markers in FGF7p‐treated mice 28 days after giving cyclophosphamide or after co‐administering a systemic AKT antagonist with FGF7p 24 h after cyclophosphamide. Vehicle‐treated and injured mice had hyperplastic urothelium, incomplete return of mature superficial cell markers, ongoing proliferation, and continued presence of basal progenitor markers 28 days after injury; conversely, FGF7p‐treated mice had normal numbers of urothelial cell layers, nearly complete return of superficial cell markers, limited proliferation and fewer basal progenitor cells 28 days post‐injury. Vehicle‐treated mice also had ectopic lumenal basal progenitor cell markers, while FGF7p had none 28 days after cyclophosphamide. Co‐administration of an AKT inhibitor largely abrogated FGF7p‐driven AKT activation and cytoprotection in urothelium 24 h after injury. Thus, FGF7p drives faster and higher fidelity urothelial repair by limiting apoptotic injury via AKT signaling, similar to full‐length FGF7. Finally, FGF7p is much less expensive to synthesize and has a longer shelf life and higher purity than FGF7. |
| first_indexed | 2024-03-08T23:53:01Z |
| format | Article |
| id | doaj.art-a8bfd03a174c475fbeda297d0a8444b9 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-08T23:53:01Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-a8bfd03a174c475fbeda297d0a8444b92023-12-13T09:35:42ZengWileyPhysiological Reports2051-817X2022-06-011012n/an/a10.14814/phy2.15358Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamideSridhar Tatarao Narla0Lori Rice1David Ostrov2Daniel Scott Bushnell3Joanne Lindsey Duara4Carlton Matthew Bates5Division of Nephrology Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USADepartment of Radiation Oncology College of Medicine University of Florida Gainesville Florida USADepartment of Pathology, Immunology, and Laboratory Medicine University of Florida College of Medicine Gainesville Florida USADivision of Nephrology Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USADivision of Neonatology, Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USADivision of Nephrology Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USAAbstract We previously identified a peptide derived from human fibroblast growth factor 7 (FGF7p) that blocks urothelial apoptosis similar to full‐length FGF7, although effects of FGF7p on urothelial repair are unknown. Also, while urothelial AKT activation downstream of FGF7p correlated with the anti‐apoptotic effects, we have not directly interrogated the role of AKT in mediating the cytoprotection. Our goal was to assess effects of FGF7p on urothelial repair and the role of AKT signaling in mediating the cytoprotective effects of FGF7p. We performed hematoxylin and eosin (H&E), TUNEL, and/or immunofluorescence (IF) staining for various markers in FGF7p‐treated mice 28 days after giving cyclophosphamide or after co‐administering a systemic AKT antagonist with FGF7p 24 h after cyclophosphamide. Vehicle‐treated and injured mice had hyperplastic urothelium, incomplete return of mature superficial cell markers, ongoing proliferation, and continued presence of basal progenitor markers 28 days after injury; conversely, FGF7p‐treated mice had normal numbers of urothelial cell layers, nearly complete return of superficial cell markers, limited proliferation and fewer basal progenitor cells 28 days post‐injury. Vehicle‐treated mice also had ectopic lumenal basal progenitor cell markers, while FGF7p had none 28 days after cyclophosphamide. Co‐administration of an AKT inhibitor largely abrogated FGF7p‐driven AKT activation and cytoprotection in urothelium 24 h after injury. Thus, FGF7p drives faster and higher fidelity urothelial repair by limiting apoptotic injury via AKT signaling, similar to full‐length FGF7. Finally, FGF7p is much less expensive to synthesize and has a longer shelf life and higher purity than FGF7.https://doi.org/10.14814/phy2.15358AKTbladder urotheliumcyclophosphamideFGF7pfibroblast growth factor 7 peptide |
| spellingShingle | Sridhar Tatarao Narla Lori Rice David Ostrov Daniel Scott Bushnell Joanne Lindsey Duara Carlton Matthew Bates Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide Physiological Reports AKT bladder urothelium cyclophosphamide FGF7p fibroblast growth factor 7 peptide |
| title | Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide |
| title_full | Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide |
| title_fullStr | Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide |
| title_full_unstemmed | Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide |
| title_short | Durability of and role of AKT in FGF7p urothelial protection against cyclophosphamide |
| title_sort | durability of and role of akt in fgf7p urothelial protection against cyclophosphamide |
| topic | AKT bladder urothelium cyclophosphamide FGF7p fibroblast growth factor 7 peptide |
| url | https://doi.org/10.14814/phy2.15358 |
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