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Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation
Saori Nishio, … , Takeshi Tokuhisa, Toshio Mochizuki
Saori Nishio, … , Takeshi Tokuhisa, Toshio Mochizuki
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):910-918. https://doi.org/10.1172/JCI22850.
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Article Nephrology

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed 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+/+ morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both Pkd1–/– and Pkd1+/+ renal tubular epithelial cells in the early stages of cystogenesis. Pkd1–/– cyst epithelial cells changed in shape from cuboidal to flat and replaced Pkd1+/+ cyst epithelial cells lost by JNK-mediated apoptosis in intermediate stages. In late-stage cysts, Pkd1–/– cells continued immortalized proliferation with downregulation of p53. These results provide a novel understanding of 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 the induction of p53 and activation of JNK.

Authors

Saori Nishio, Masahiko Hatano, Michio Nagata, Shigeo Horie, Takao Koike, Takeshi Tokuhisa, Toshio Mochizuki

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Figure 5

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Proliferation of Pkd1–/– cyst epithelial cells. (A) A kidney from a P17 ...
Proliferation of Pkd1–/– cyst epithelial cells. (A) A kidney from a P17 Pkd1–/–/LZ+ mouse was stained with β-gal and counterstained with Nuclear Fast Red. LZ+ epithelial cells occasionally showed focal hyperplastic features such as micropolyps. Original magnification, ×400. (B) A kidney froma P12 Pkd1–/–/LZ+ mouse was stained with an anti-PCNA. Some cuboidal LZ+ cyst epithelial cells were accompanied by PCNA expression. Original magnification, ×400. (C) Expression of p21 and p53 in the kidneys of Pkd1–/– mice at E16.5 and Pkd1–/–/LZ+ mice 1 month of age. The amount of p21 and p53 in kidneys was examined using Western blot. Actin was used as a loading control for protein. Data presented are 1 representative of 4 independent experiments. (D) Kidneys of P12 Pkd1–/–/LZ+ and P12 wild-type mice were stained with anti-p53. Expression of p53 was detected in the flat epithelial cells (white arrowhead) but was significantly decreased in the cuboidal cyst epithelial cells (black arrowheads) of the Pkd1–/–/LZ+ mouse. Original magnification, ×400. (E–G) The proliferation of cyst epithelial cells in vitro. A single nephron isolated by microdissection from the kidney of a Pkd1–/–/LZ+ mouse at E17.5 was cultured in collagen gel for 18 hours. (F and G) Higher magnifications of the boxed area above. Both LZ+ and Pkd1–/– (LZ–) cells proliferated. Scale bars: 100 μm.

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