| RRC ID |
43525
|
| 著者 |
Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, Miyoshi J, Takai Y, Fujita T.
|
| タイトル |
Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease.
|
| ジャーナル |
Nat Med
|
| Abstract |
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.
|
| 巻・号 |
14(12)
|
| ページ |
1370-6
|
| 公開日 |
2008-12-1
|
| DOI |
10.1038/nm.1879
|
| PII |
nm.1879
|
| PMID |
19029984
|
| MeSH |
Aminoquinolines / therapeutic use
Animals
Cell Line
Humans
Kidney Diseases / drug therapy*
Kidney Diseases / metabolism*
Mice
Mice, Knockout
Microscopy, Electron
Proteinuria / drug therapy*
Proteinuria / metabolism*
Pyrimidines / therapeutic use
Receptors, Mineralocorticoid / metabolism*
Signal Transduction
rac1 GTP-Binding Protein / genetics
rac1 GTP-Binding Protein / metabolism*
|
| IF |
36.13
|
| 引用数 |
265
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
293(RCB1637) |
