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Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease.
MedLine Citation:
PMID:  23296296     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Miki Nagase; Toshiro Fujita
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-08
Journal Detail:
Title:  Nature reviews. Nephrology     Volume:  -     ISSN:  1759-507X     ISO Abbreviation:  Nat Rev Nephrol     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101500081     Medline TA:  Nat Rev Nephrol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
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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