| Podocyte-specific loss of Cdc42 leads to congenital nephropathy. | |
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MedLine Citation:
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PMID: 22518006 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton. The prototypic members of this family are Cdc42, Rac1, and RhoA; these GTPases contribute to the breakdown of glomerular filtration and the resultant proteinuria, but their functions in normal podocyte physiology remain poorly understood. Here, mice lacking Cdc42 in podocytes developed congenital nephropathy and died as a result of renal failure within 2 weeks after birth. In contrast, mice lacking Rac1 or RhoA in podocytes were overtly normal and lived to adulthood. Kidneys from Cdc42-mutant mice exhibited protein-filled microcysts with hallmarks of collapsing glomerulopathy, as well as extensive effacement of podocyte foot processes with abnormal junctional complexes. Furthermore, we observed aberrant expression of several podocyte markers and cell polarity proteins in the absence of Cdc42, indicating a disruption of the slit diaphragm. Kidneys from Rac1- and RhoA-mutant mice, however, had normal glomerular morphology and intact foot processes. A nephrin clustering assay suggested that Cdc42 deficiency, but not Rac1 or RhoA deficiency, impairs the polymerization of actin at sites of nephrin aggregates. Taken together, these data highlight the physiological importance of Cdc42, but not Rac1 or RhoA, in establishing podocyte architecture and glomerular function. |
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Authors:
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Rizaldy P Scott; Steve P Hawley; Julie Ruston; Jianmei Du; Cord Brakebusch; Nina Jones; Tony Pawson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-04-19 |
Journal Detail:
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Title: Journal of the American Society of Nephrology : JASN Volume: 23 ISSN: 1533-3450 ISO Abbreviation: J. Am. Soc. Nephrol. Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-07-03 Completed Date: 2012-10-23 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9013836 Medline TA: J Am Soc Nephrol Country: United States |
Other Details:
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Languages: eng Pagination: 1149-54 Citation Subset: IM |
Affiliation:
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Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Disease Models, Animal Female Glomerular Filtration Barrier / metabolism Kidney Diseases / congenital*, etiology*, metabolism Membrane Proteins / metabolism Mice Mice, Knockout Mice, Transgenic Podocytes / metabolism*, pathology Pregnancy cdc42 GTP-Binding Protein / deficiency*, genetics, metabolism rac1 GTP-Binding Protein / deficiency, genetics, metabolism rho GTP-Binding Proteins / deficiency, genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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MOP-57793//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Membrane Proteins; 0/nephrin; EC 3.6.5.2/RhoA protein, mouse; EC 3.6.5.2/cdc42 GTP-Binding Protein; EC 3.6.5.2/rac1 GTP-Binding Protein; EC 3.6.5.2/rho GTP-Binding Proteins |
| Comments/Corrections | |
Comment In:
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J Am Soc Nephrol. 2012 Jul;23(7):1128-9
[PMID:
22677549
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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