| Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease. | |
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MedLine Citation:
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PMID: 23296296    Owner: NLM    Status: Publisher    |
Abstract/OtherAbstract:
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The Rho-family small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), has been implicated in renal and cardiac disease. Rac1 activation in podocytes has been shown in several models of proteinuric kidney disease and a concept involving motile podocytes has been proposed. Evidence also exists for a critical role of Rac1-mediated oxidative stress in cardiac hypertrophy, cardiomyopathy and arrhythmia, and of the aldosterone-mineralocorticoid-receptor system in proteinuria and cardiac disorders. However, plasma aldosterone concentrations are not always increased in these conditions and the mechanisms of mineralocorticoid-receptor overactivation are difficult to determine. Using knockout mice, we identified a novel mechanism of Rac1-mediated podocyte impairment; Rac1 potentiates the activity of the mineralocorticoid receptor, thereby accelerating podocyte injury. We subsequently demonstrated that the Rac1-mineralocorticoid-receptor pathway contributes to ligand-independent mineralocorticoid-receptor activation in several animal models of kidney and cardiac injury. Hyperkalaemia is a major concern associated with the use of mineralocorticoid-receptor antagonists; however, agents that modulate the activity of the Rac1-mineralocorticoid-receptor pathway in target cells, such as cell-type-specific Rac inhibitors and selective mineralocorticoid-receptor modulators, could potentially be novel therapeutic candidates with high efficacy and a low risk of adverse effects in patients with renal and cardiac diseases. |
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Authors:
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Miki Nagase; Toshiro Fujita |
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Publication Detail:
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Type:Â JOURNAL ARTICLE Â Â Â Date:Â 2013-1-08 |
Journal Detail:
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Title: Nature reviews. Nephrology    Volume: -    ISSN: 1759-507X    ISO Abbreviation: Nat Rev Nephrol    Publication Date: 2013 Jan |
Date Detail:
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Created Date:Â 2013-1-8 Â Â Â Completed Date:Â - Â Â Â Revised Date:Â - Â Â Â |
Medline Journal Info:
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Nlm Unique ID: 101500081    Medline TA: Nat Rev Nephrol    Country: -    |
Other Details:
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Languages:Â ENG Â Â Â Pagination:Â - Â Â Â Citation Subset:Â - Â Â Â |
Affiliation:
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Division of Chronic Kidney Disease, Department of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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