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NDT Advance Access originally published online on September 2, 2005
Nephrology Dialysis Transplantation 2005 20(11):2368-2375; doi:10.1093/ndt/gfi040
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Article

Role of keratinocyte growth factor in the pathogenesis of autosomal dominant polycystic kidney disease

Changlin Mei, Zhiguo Mao, Xuefei Shen, Wenjing Wang, Bing Dai, Bing Tang, Yumei Wu, Yang Cao, Shuzhong Zhang, Haidan Zhao and Tianmei Sun

Division of Nephrology, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China

Correspondence and offprint requests to: Changlin Mei, Division of Nephrology, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, People's Republic of China. Email: chlmei1954{at}126.com

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 P21wafl 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 P21wafl 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 P21wafl genes. KGF may play a role in pathogenesis of ADPKD.

Keywords: autosomal dominant polycystic kidney disease (ADPKD); cell cycle; cyclin; keratinocyte growth factor (KGF); proliferation


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[Abstract] [Full Text] [PDF]


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