title: Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease.
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.
authors.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.
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000818:Animals; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D018161:Receptors, Mineralocorticoid; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein