title: Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway.
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.
authors.affiliation: Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Shibata
authors.forename: ShengYu
authors.initials: S
authors.lastname: Mu
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kawarazaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Muraoka
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Yoshida
authors.forename: Wakako
authors.initials: W
authors.lastname: Kawarazaki
authors.forename: Maki
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ayuzawa
authors.forename: Jun
authors.initials: J
authors.lastname: Miyoshi
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takai
authors.forename: Akira
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ando
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D006973:Hypertension / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D020830:rac1 GTP-Binding Protein