Abstract
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.
Key Points
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Rac1 activation has been implicated in podocyte injury, cardiac dysfunction and other diseases
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Rac1 activation in glomerular podocytes might be associated with increased podocyte motility and foot process effacement
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Rac1 potentiates the activity of the mineralocorticoid receptor in a ligand-independent manner, thereby accelerating podocyte impairment
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Ligand-independent mineralocorticoid-receptor activation is mediated by Rac1 in several animal models of salt-sensitive hypertension and kidney disease
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Rac1–mineralocorticoid-receptor crosstalk contributes to the cardiac injury induced by reactive oxygen species
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Rac inhibitors and selective mineralocorticoid-receptor modulators that regulate the activity of the Rac1–mineralocorticoid-receptor pathway might be novel candidates for the treatment of renal and cardiac disease
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Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 24390214 [M. Nagase] and No. 21229012 [T. Fujita]).
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M. Nagase researched the data for the article and wrote the manuscript. T. Fujita made a substantial contribution to discussions of the content and reviewed and edited the manuscript before submission.
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Nagase, M., Fujita, T. Role of Rac1–mineralocorticoid-receptor signalling in renal and cardiac disease. Nat Rev Nephrol 9, 86–98 (2013). https://doi.org/10.1038/nrneph.2012.282
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DOI: https://doi.org/10.1038/nrneph.2012.282
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