Compensatory paracrine mechanisms that define the urothelial response to injury in partial bladder outlet obstruction.
Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo. To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.
Lendvay
Thomas S
TS
Program in Human Urothelial Biology, Seattle Children's Hospital Research Institute, Seattle, WA 98105, USA.
Sweet
Robert
R
Han
Chang-Hee
CH
Soygur
Tarkan
T
Cheng
Jan-Fan
JF
Plaire
J Chadwick
JC
Charleston
Jay S
JS
Charleston
Lynne B
LB
Bagai
Shelly
S
Cochrane
Kimberly
K
Rubio
Eric
E
Bassuk
James A
JA
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D019899:Paracrine Communication / Q000502:physiology*; D014162:Transfection; D001748:Urinary Bladder Neck Obstruction / Q000378:metabolism* / Q000473:pathology; D019459:Urothelium / Q000378:metabolism* / Q000473:pathology
C496463:FGF10 protein, human; C496453:FGF7 protein, human; C496464:Fgf10 protein, mouse; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7