title: Role of angiotensin II-mediated AMPK inactivation on obesity-related salt-sensitive hypertension.
abstract: Salt-sensitive hypertension is a characteristic of the metabolic syndrome. Given the links to cardiovascular events, the mechanisms underlying sodium metabolism may represent an important therapeutic target for this disorder. Angiotensin II (AII) is a key peptide underlying sodium retention. However, 5'AMP-activated protein kinase (AMPK) has also been reported to participate in the regulation of ion transport. In this study we examined the relationship between AII and AMPK on the development of hypertension in two salt-sensitive mouse models. In the first model, the mice were maintained on a high-fat diet (HFD) for 12 weeks, in order to develop features similar to the metabolic syndrome, including salt-sensitive hypertension. HFD-induced obese mice showed elevated systolic blood pressure and lower sodium excretion in response to salt loading, along with an increase in AII contents and inactivation of AMPK in the kidney, which were significantly improved by the treatment of an angiotensin II antagonist, losartan, for 2 weeks. To clarify the effects of AII, a second group of mice was infused with AII via an osmotic pump, which led to higher systolic blood pressure, and decreases in urinary sodium excretion and the expression of AMPK, in a manner similar to those observed in the HFD mice. However, treatment with an AMPK activator, metformin, improved the changes induced by the AII, suggesting that AII induced sodium retention works by acting on AMPK activity. Finally, we evaluated the changes in salt-sensitivity by performing 2-week salt loading experiments with or without metformin. AII infusion elevated blood pressure by salt loading but metformin prevented it. These findings indicate that AII suppresses AMPK activity in the kidney, leading to sodium retention and enhanced salt-sensitivity, and that AMPK activation may represent a new therapeutic target for obesity-related salt-sensitive hypertension.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Deji
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Keiji
authors.initials: K
authors.lastname: Isshiki
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Araki
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D012982:Sodium, Dietary / Q000009:adverse effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D012982:Sodium, Dietary; D000804:Angiotensin II; D008687:Metformin; D012964:Sodium; D055372:AMP-Activated Protein Kinases; D019808:Losartan