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Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway

Shibata, Shigeru ; Mu, ShengYu ; 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

The Journal of clinical investigation, 2011-08, Vol.121 (8), p.3233-3243 [Periódico revisado por pares]

United States: American Society for Clinical Investigation

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Título:
Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway
Autor: Shibata, Shigeru ; Mu, ShengYu ; 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
Assuntos: Aldosterone - metabolism ; Analysis ; Animals ; Biomedical research ; Blood pressure ; Development and progression ; Diet ; Guanosine triphosphatase ; Health aspects ; Hormone receptors ; Hypertension ; Hypertension - metabolism ; Kidney - metabolism ; Kidney diseases ; Kidney Diseases - metabolism ; Kinases ; Male ; Mice ; Mice, Transgenic ; Models, Biological ; Pathogenesis ; Physiological aspects ; Potassium ; Proteinuria - metabolism ; rac1 GTP-Binding Protein - metabolism ; Rats ; Rats, Inbred Dahl ; Receptors, Mineralocorticoid - metabolism ; Rodents ; Salt ; Sodium ; Sodium Chloride, Dietary - pharmacology
É parte de: The Journal of clinical investigation, 2011-08, Vol.121 (8), p.3233-3243
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Authorship note: Shigeru Shibata, ShengYu Mu, and Hiroo Kawarazaki contributed equally to this work.
Descrição: 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.
Editor: United States: American Society for Clinical Investigation
Idioma: Inglês

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Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway

Shibata, Shigeru ; Mu, ShengYu ; 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

United States: American Society for Clinical Investigation

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