| Cystogenesis in ARPKD results from increased apoptosis in collecting duct epithelial cells of Pkhd1 mutant kidneys. | |
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MedLine Citation:
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PMID: 20875407 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in the PKHD1 gene result in autosomal recessive polycystic kidney disease (ARPKD) in humans. To determine the molecular mechanism of the cystogenesis in ARPKD, we recently generated a mouse model for ARPKD that carries a targeted mutation in the mouse orthologue of human PKHD1. The homozygous mutant mice display hepatorenal cysts whose phenotypes are similar to those of human ARPKD patients. By littermates of this mouse, we developed two immortalized renal collecting duct cell lines with Pkhd1 and two without. Under nonpermissive culture conditions, the Pkhd1(-/-) renal cells displayed aberrant cell-cell contacts and tubulomorphogenesis. The Pkhd1(-/-) cells also showed significantly reduced cell proliferation and elevated apoptosis. To validate this finding in vivo, we examined proliferation and apoptosis in the kidneys of Pkhd1(-/-) mice and their wildtype littermates. Using proliferation (PCNA and Histone-3) and apoptosis (TUNEL and caspase-3) markers, similar results were obtained in the Pkhd1(-/-) kidney tissues as in the cells. To identify the molecular basis of these findings, we analyzed the effect of Pkhd1 loss on multiple putative signaling regulators. We demonstrated that the loss of Pkhd1 disrupts multiple major phosphorylations of focal adhesion kinase (FAK), and these disruptions either inhibit the Ras/C-Raf pathways to suppress MEK/ERK activity and ultimately reduce cell proliferation, or suppress PDK1/AKT to upregulate Bax/caspase-9/caspase-3 and promote apoptosis. Our findings indicate that apoptosis may be a major player in the cyst formation in ARPKD, which may lead to new therapeutic strategies for human ARPKD. |
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Authors:
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Bo Hu; Xiusheng He; Ao Li; Qingchao Qiu; Cunxi Li; Dan Liang; Ping Zhao; Jie Ma; Robert J Coffey; Qimin Zhan; Guanqing Wu |
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Publication Detail:
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Type: Comparative Study; In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-25 |
Journal Detail:
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Title: Experimental cell research Volume: 317 ISSN: 1090-2422 ISO Abbreviation: Exp. Cell Res. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-11-29 Completed Date: 2011-01-13 Revised Date: 2011-09-22 |
Medline Journal Info:
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Nlm Unique ID: 0373226 Medline TA: Exp Cell Res Country: United States |
Other Details:
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Languages: eng Pagination: 173-87 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Cancer Research Institute, University of South China, Hengyang, Hunan, 421001, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / genetics* Caspase 3 / genetics, metabolism Caspase 9 / genetics, metabolism Cell Line, Transformed Cell Proliferation Crosses, Genetic Cysts / genetics Disease Models, Animal Epithelial Cells / metabolism* Genes, cdc Genotype Humans Kidney / metabolism* Kidney Tubules, Collecting / metabolism Mice Mice, Congenic Mice, Inbred C57BL Mice, Knockout Mutation Phenotype Polycystic Kidney, Autosomal Recessive / genetics*, metabolism, pathology Proto-Oncogene Proteins c-akt / genetics, metabolism Receptors, Cell Surface / genetics* Signal Transduction / genetics |
| Grant Support | |
ID/Acronym/Agency:
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5P50 CA095103/CA/NCI NIH HHS; DK062373/DK/NIDDK NIH HHS; DK71090/DK/NIDDK NIH HHS; R01 DK062373-01A1/DK/NIDDK NIH HHS; R01 DK062373-02/DK/NIDDK NIH HHS; R01 DK062373-03/DK/NIDDK NIH HHS; R01 DK062373-04/DK/NIDDK NIH HHS; R01 DK062373-05/DK/NIDDK NIH HHS; R01 DK071090-01/DK/NIDDK NIH HHS; R01 DK071090-02/DK/NIDDK NIH HHS; R01 DK071090-03/DK/NIDDK NIH HHS; R01 DK071090-04/DK/NIDDK NIH HHS; R21 DK065111-01/DK/NIDDK NIH HHS; R21 DK065111-02/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/PKHD1 protein, human; 0/Pkhd1 protein, mouse; 0/Receptors, Cell Surface; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9 |
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