Cystogenesis in the gene targeting mice of autosomal dominant polycystic kidney disease (ADPKD)
| Project/Area Number |
15590838
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Kidney internal medicine
|
|---|
| Research Institution | HOKKAIDO UNIVERSITY |
|---|
Principal Investigator |
MOCHIZUKI Toshio Hokkaido Univ., Grad.School of Medicine, Assist.Prof., 病院, 講師 (00277120)
|
|---|
| 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)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| 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)
|
|---|
| Keywords | Polycystic kidney / ADPKD / PKD1 / knockout mouse / knockout chimera mouse |
|---|
| 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.
|
Report
(3 results)
Research Products
(3 results)
