| Project/Area Number |
15590838
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
MOCHIZUKI Toshio Hokkaido Univ., Grad.School of Medicine, Assist.Prof., 病院, 講師 (00277120)
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| Co-Investigator(Kenkyū-buntansha) |
HATANO Masahiko Chiba Univ., Biomedical Center, Associate Prof., バイオメディカルセンター, 助教授 (20208523)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Polycystic kidney / ADPKD / PKD1 / knockout mouse / knockout chimera mouse |
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| Research Abstract |
Autosomal dominant polycystic kidney disease (ADPKD) is a most common human monogenic genetic disorder characterized by progressive bilateral renal cysts and develops renal insufficiency. Cystogenesis of ADPKD is considered to be a monoclonal proliferation of PKD-deficient (PKD^<-/->) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1^<-/-> ES cells and Pkd1^<+/+> morula from ROSA26 mice. Like human ADPKD, these mice developed cysts in kidney, liver and pancreas. Surprisingly, cyst epithelium in the kidney was composed of both Pkd1^<-/-> and Pkd1^<+/+> renal tubular epithelial cells at early stages of cystogenesis. Pkd1^<-/-> cyst epithelial cells changed shape from cuboidal to flat and replaced Pkd1^<+/+> cyst epithelial cells lost by JNK-mediated apoptosis at intermediate stages. In late stage cysts, Pkd1^<-/-> cells continued immortalized proliferation with down-regulation of p53. These results provide a novel scenario in the cystogenesis of ADPKD patients. Furthermore, immortalized proliferation without induction of p53 was frequently observed in 3T3 type culture of mouse embryonic fibroblasts from Pkd1^<-/-> mice. Thus, Pkd1 plays a role in preventing immortalized proliferation of renal tubular epithelial cells through induction of p53 and activation of JNK.
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