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Cyst Formation in Kidney via B-Raf Signaling in the PKD2 Transgenic Mice

Authors
Park, Eun YoungSung, Young HoonYang, Moon HeeNoh, Ji YeunPark, So YoungLee, Tae YoungYook, Yeon JooYoo, Kyung HyunRoh, Kyung JinKim, IngyuHwang, Young-HwanOh, Goo TaegSeong, Je KyungAhn, CurieLee, Han-WoongPark, Jong Hoon
Issue Date
Mar-2009
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.284, no.11, pp.7214 - 7222
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume
284
Number
11
Start Page
7214
End Page
7222
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/13804
DOI
10.1074/jbc.M805890200
ISSN
0021-9258
Abstract
The pathogenic mechanisms of human autosomal dominant polycystic kidney disease (ADPKD) have been well known to include the mutational inactivation of PKD2. Although haploinsufficiency and loss of heterozygosity at the Pkd2 locus can cause cyst formation in mice, polycystin-2 is frequently expressed in the renal cyst of human ADPKD, raising the possibility that deregulated activation of PKD2 may be associated with the cystogenesis of human ADPKD. To determine whether increased PKD2 expression is physiologically pathogenic, we generated PKD2-overexpressing transgenic mice. These mice developed typical renal cysts and an increase of proliferation and apoptosis, which are reflective of the human ADPKD phenotype. These manifestations were first observed at six months, and progressed with age. In addition, we found that ERK activation was induced by PKD2 overexpression via B-Raf signaling, providing a possible molecular mechanism of cystogenesis. In PKD2 transgenic mice, B-Raf/MEK/ERK sequential signaling was up-regulated. Additionally, the transgenic human polycystin-2 partially rescues the lethality of Pkd2 knock-out mice and therefore demonstrates that the transgene generated a functional product. Functional strengthening or deregulated activation of PKD2 may be a direct cause of ADPKD. The present study provides evidence for an in vivo role of overexpressed PKD2 in cyst formation. This transgenic mouse model should provide new insights into the pathogenic mechanism of human ADPKD.
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