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- Title
Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway.
- Authors
Shibata, Shigeru; ShengYu Mu; Kawarazaki, Hiroo; Muraoka, Kazuhiko; Ishizawa, Ken-ichi; Yoshida, Shigetaka; Kawarazaki, Wakako; Takeuchi, Maki; Ayuzawa, Nobuhiro; Miyoshi, Jun; Takai, Yoshimi; Ishikawa, Akira; Shimosawa, Tatsuo; Ando, Katsuyuki; Nagase, Miki; Fujita, Toshiro; Mu, ShengYu
- Abstract
Hypertension is a leading contributor to cardiovascular mortality worldwide. Despite this, its underlying mechanism(s) and the role of excess salt in cardiorenal dysfunction are unclear. Previously, we have identified cross-talk between mineralocorticoid receptor (MR), a nuclear transcription factor regulated by the steroid aldosterone, and the small GTPase Rac1, which is implicated in proteinuric kidney disease. We here show that high-salt loading activates Rac1 in the kidneys in rodent models of salt-sensitive hypertension, leading to blood pressure elevation and renal injury via an MR-dependent pathway. We found that a high-salt diet caused renal Rac1 upregulation in salt-sensitive Dahl (Dahl-S) rats and downregulation in salt-insensitive Dahl (Dahl-R) rats. Despite a reduction of serum aldosterone levels, salt-loaded Dahl-S rats showed increased MR signaling in the kidneys, and Rac1 inhibition prevented hypertension and renal damage with MR repression. We further demonstrated in aldosterone-infused rats as well as adrenalectomized Dahl-S rats with aldosterone supplementation that salt-induced Rac1 and aldosterone acted interdependently to cause MR overactivity and hypertension. Finally, we confirmed the key role of Rac1 in modulating salt susceptibility in mice lacking Rho GDP-dissociation inhibitor α. Therefore, our data identify Rac1 as a determinant of salt sensitivity and provide insights into the mechanism of salt-induced hypertension and kidney injury.
- Subjects
GUANOSINE triphosphatase; ANIMAL models in research; HYPERTENSION; MINERALOCORTICOIDS; KIDNEY disease treatments; ALDOSTERONE; LABORATORY mice; PROTEIN metabolism; SALT; BIOLOGICAL models; RESEARCH; KIDNEYS; ANIMAL experimentation; RESEARCH methodology; CELL receptors; MEDICAL cooperation; EVALUATION research; KIDNEY diseases; RATS; COMPARATIVE studies; PROTEINURIA; MICE
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 8, p3233
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI43124