Role of ERK signaling in bladder urothelium in response to cyclophosphamide injury. Issue 14 (19th July 2022)

• Record Type: Journal Article
• Authors: Narla, Sridhar Tatarao; Duara, Joanne Lindsey; Bushnell, Daniel Scott; Nouraie, Mehdi; Holden, Jacqueline; Pfister, Katherine; Lucas, Peter C.; Sims‐Lucas, Sunder; Bates, Carlton Matthew
• Is Part Of: Physiological reports. Volume 10:Issue 14(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-19
• Subjects: bladder -- cyclophosphamide -- ERK -- fibroblast growth factor receptor 2 -- urothelium; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.15378
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: Mice with inducible urothelial deletion of fibroblast growth factor receptor 2 ( ShhCreERT2;Fgfr2 Fl/Fl ) injured with cyclophosphamide had aberrant basal cell endoreplication and poor regeneration. The endoreplication correlated with an absence of phosphorylated (activated) ERK expression in urothelium. We assessed whether inhibiting ERK activity phenocopied the urothelial defects in injured Fgfr2 mutant mice. We co‐administered cyclophosphamide and an ERK inhibitor (ERKi) systemically in mice and assessed general histology and immunofluorescence for various markers post injury. Since AKT also signals downstream of FGFR2, we assessed effects of an AKT inhibitor (AKTi) on cyclophosphamide injury. ERK knockdown did not affect urothelial injury or proliferation 24 h after cyclophosphamide. Conversely, ERK inhibition led to larger basal cell nuclei, more submucosal hemorrhage and attenuated uroplakin staining 3 days after injury versus vehicle‐treated mice. Compared to vehicle‐treated mice, ERKi‐treated mice had a trend for more Ki67 + urothelial cells and had statistically fewer phospho‐Histone H3 + cells normalized to Ki67 and higher basal cell DNA content, consistent with endoreplication 3 days after injury. Ten days after injury, ERKi‐treated mice still had signs of poor urothelial regeneration with absent or aberrant expression of differentiation markers and ectopic lumenal expression of keratin 14 (basal progenitor marker). Co‐administration of the AKTi led to no apparent urothelial defects 3 days after cyclophosphamide. Thus, ERK knockdown (but not AKT knockdown) leads to urothelial regenerative responses after cyclophosphamide reminiscent of Fgfr2 mutant mice. Together, it appears that FGFR2 acts through ERK to prevent aberrant urothelial basal cell endoreplication and ensure normal regeneration after cyclophosphamide. Abstract : Deletion of fibroblast growth factor receptor 2 in mouse urothelium leads to pathological endoreplication and poor repair after cyclophosphamide. Mice with knockdown of ERK have a similar pathological response to cyclophosphamide while knockdown of AKT causes no defects. Thus FGFR2 likely signals via ERK to suppress urothelial maladaptive responses to cyclophosphamide.