Access
To read this story in full you will need to login or make a payment (see right).
Letter
Nature Medicine 14, 1370 - 1376 (2008)
Published online: 23 November 2008 | doi:10.1038/nm.1879
Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease
Shigeru Shibata1,6, Miki Nagase1,6, Shigetaka Yoshida1, Wakako Kawarazaki1, Hidetake Kurihara2, Hirotoshi Tanaka3, Jun Miyoshi4, Yoshimi Takai5 & Toshiro Fujita1
Abstract
Blockade of mineralocorticoid receptor has been shown to improve the clinical outcomes of proteinuric kidney diseases1, 2. 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-
(Arhgdia-/- mice)3, 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 inhibitor4, 5 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.
To read this story in full you will need to login or make a payment (see right).
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Manganese Superoxide Dismutase Affects Cytochrome c Release and Caspase-9 Activation After Transient Focal Cerebral Ischemia in MiceJournal of Cerebral Blood Flow & Metabolism Original Article
Relationship between Blood Pressure and Chronic Kidney Disease in the Japanese Population: The Lower the Better Even in Individuals without Hypertension?Hypertension Research Original Article
See all 17 matches for Research