Blockade of
mineralocorticoid receptor has been shown to improve the clinical outcomes of proteinuric
kidney diseases. However, little is known about the regulation of
mineralocorticoid receptor-dependent transcriptional activity in renal disease. Here we identify a new role for Rac1, a member of the Rho family
GTPases, as a potent activator of
mineralocorticoid receptor signal transduction both in vitro and in vivo. Transient transfection assays in HEK 293 cells revealed that constitutively active Rac1 (CA-Rac1) enhanced
mineralocorticoid receptor-dependent reporter activity, which was accompanied by increased nuclear translocation of
mineralocorticoid receptor. CA-Rac1 facilitated
mineralocorticoid receptor nuclear accumulation also in podocytes via
p21-activated kinase phosphorylation. In mice lacking Rho
GDP-dissociation inhibitor-alpha (Arhgdia(-/-) mice), renal abnormalities, including heavy
albuminuria and podocyte damage, were associated with increased Rac1 (but not RhoA) and
mineralocorticoid receptor signaling in the kidney, without alteration in systemic
aldosterone status. Pharmacological intervention with a Rac-specific small-molecule inhibitor diminished
mineralocorticoid receptor overactivity and renal damage in this model. Furthermore,
albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by
mineralocorticoid receptor blockade, confirming the pathological role of Rac1-mineralocorticoid receptor interaction. Our results provide evidence that signaling cross-talk between Rac1 and
mineralocorticoid receptor modulates
mineralocorticoid receptor activity and identify Rac1 as a therapeutic target for
chronic kidney disease.