Intrarenal urothelium proliferation: an unexpected early event following ischemic injury.
Identification of renal cell progenitors and recognition of the events contributing to cell regeneration following ischemia-reperfusion injury (IRI) are a major challenge. In a mouse model of unilateral renal IRI, we demonstrated that the first cells to proliferate within injured kidneys were urothelial cells expressing the progenitor cell marker cytokeratin 14. A systematic cutting of the injured kidney revealed that these urothelial cells were located in the deep cortex at the corticomedullary junction in the vicinity of lobar vessels. Contrary to multilayered bladder urothelium, these intrarenal urothelial cells located in the upper part of the medulla constitute a monolayered barrier and express among uroplakins only uroplakin III. However, like bladder progenitors, intrarenal urothelial cells proliferated through a FGF receptor-2 (FGFR2)-mediated process. They strongly expressed FGFR2 and proliferated in vivo after recombinant FGF7 administration to control mice. In addition, IRI led to FGFR phosphorylation together with the selective upregulation of FGF7 and FGF2. Conversely, by day 2 following IRI, renal urothelial cell proliferation was significantly inhibited by FGFR2 antisense oligonucleotide administration into an intrarenal urinary space. Of notice, no significant migration of these early dividing urothelial cells was detected in the cortex within 7 days following IRI. Thus our data show that following IRI, proliferation of urothelial cells is mediated by the FGFR2 pathway and precedes tubular cell proliferation, indicating a particular sensitivity of this structure to changes caused by the ischemic process.
Vinsonneau
C
C
INSERM UMRS, Université Pierre et Marie Curie Paris, France.
Girshovich
A
A
M'rad
M Ben
MB
Perez
J
J
Mesnard
L
L
Vandermersch
S
S
Placier
S
S
Letavernier
E
E
Baud
L
L
Haymann
J-P
JP
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000502:physiology; D007672:Kidney Cortex / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D019459:Urothelium / Q000473:pathology
C496454:Fgf7 protein, mouse; D051523:Fibroblast Growth Factor 7; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2