Role of keratinocyte growth factor in the pathogenesis of autosomal dominant polycystic kidney disease.
BACKGROUND
Previous studies have shown that the expression and distribution of keratinocyte growth factor (KGF), also known as FGF-7 (fibroblast growth factor-7) or HBGF-7 (heparin-binding growth factor-7), may be implicated in kidney cyst formation and expansion. However, there are no data on KGF expression in human autosomal dominant polycystic kidney disease (ADPKD) tissue, and it is unknown whether it affects ADPKD cyst-lining epithelial cell epithelial cell proliferation.


METHODS
The expression and distribution of KGF and KGF receptor (KGFR) mRNA in ADPKD cystic and normal kidney tissues were examined using quantitative real-time polymerase chain reaction (PCR) and in situ hybridization. KGF and KGFR protein expression in the above tissues was analysed by immunohistochemistry and western blot. The effect of KGF on cyst-lining epithelial cell proliferation was assessed by MTT assay, and its effect on the cyst-lining epithelial cell cycle was analysed by flow cytometry. The effect of KGF on cyclin D1 and P21(wafl) gene expression in cyst-lining epithelial cells was also determined.


RESULTS
KGF and KGFR mRNA expression in ADPKD cysts was higher than in normal kidney tissues. KGF and KGFR protein expression was also higher in ADPKD cysts and was localized to cyst-lining epithelial cells, tubular and interstitial cells. In vitro experiments revealed that KGF promoted cyst-lining epithelial cell proliferation, and decreased the ratio of G0/G1 phase but increased that of S phase. In response to KGF, the expression of the cyclin D1 gene in cyst-lining epithelial cells increased markedly while P21(wafl) expression decreased.


CONCLUSIONS
KGF and KGFR expression was upregulated in ADPKD kidney tissues. KGF stimulated the proliferation of cyst-lining epithelial cell in vitro by regulating the expression of cyclin D1 and P21(wafl) genes. KGF may play a role in pathogenesis of ADPKD.
Mei
Changlin
C
Division of Nephrology, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China. chlmei1954@126.com
Mao
Zhiguo
Z
Shen
Xuefei
X
Wang
Wenjing
W
Dai
Bing
B
Tang
Bing
B
Wu
Yumei
Y
Cao
Yang
Y
Zhang
Shuzhong
S
Zhao
Haidan
H
Sun
Tianmei
T
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000096:biosynthesis / Q000235:genetics*; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies
D012333:RNA, Messenger; D051523:Fibroblast Growth Factor 7; D019938:Cyclin D1; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor