title: High aminopeptidase A activity contributes to blood pressure control inob/obmice by AT2receptor-dependent mechanism.
abstract: Obesity is assumed to be a major cause of human essential hypertension; however, the mechanisms responsible for weight-related increase in blood pressure (BP) are not fully understood. The prevalence of hypertension induced by obesity has grown over the years, and the role of the renin-angiotensin-aldosterone system (RAAS) in this process continues to be elucidated. In this scenario, theob/obmice are a genetic obesity model generally used for metabolic disorder studies. These mice are normotensive even though they present several metabolic conditions that predispose them to hypertension. Although the normotensive trait in these mice is associated with the poor activation of sympathetic nervous system by the lack of leptin, we demonstrated thatob/obmice present massively increased aminopeptidase A (APA) activity in the circulation. APA enzyme metabolizes angiotensin (ANG) II into ANG III, a peptide associated with intrarenal angiotensin type 2 (AT2) receptor activation and induction of natriuresis. In these mice, we found increased ANG-III levels in the circulation, high AT2receptor expression in the kidney, and enhanced natriuresis. AT2receptor blocking and APA inhibition increased BP, suggesting the ANG III-AT2receptor axis as a complementary BP control mechanism. Circulating APA activity was significantly reduced by weight loss independently of leptin, indicating the role of fat tissue in APA production. Therefore, in this study we provide new data supporting the role of APA in BP control inob/obmouse strain. These findings improve our comprehension about obesity-related hypertension and suggest new tools for its treatment.NEW & NOTEWORTHYIn this study, we reported an increased angiotensin III generation in the circulation ofob/obmice caused by a high aminopeptidase A activity. These findings are associated with an increased natriuresis found in these mice and support the role of renin-angiotensin-aldosterone system as additional mechanism regulating blood pressure in this genetic obese strain.
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Morais
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Hilzendeger
authors.affiliation: Departamento de Psicobiologia, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Visniauskas
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Mihail
authors.initials: M
authors.lastname: Todiras
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Ronaldo C
authors.initials: RC
authors.lastname: Araújo
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Clovis R
authors.initials: CR
authors.lastname: Nakaie
authors.affiliation: Departamento de Psicobiologia, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Jair R
authors.initials: JR
authors.lastname: Chagas
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
authors.forename: Adriana K
authors.initials: AK
authors.lastname: Carmona
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Charité University Medicine Berlin, Berlin, Germany.|German Center for Cardiovascular Research, Berlin, Germany; and.|Institute for Biology, University of Lübeck, Lübeck, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil; jbpesquero@gmail.com.
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000809:Angiotensins / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D031204:Caloric Restriction; D006152:Cyclic GMP / Q000378:metabolism; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043384:Glutamyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D020738:Leptin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000503:physiopathology*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012964:Sodium / Q000652:urine
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000809:Angiotensins; D004791:Enzyme Inhibitors; D020738:Leptin; D044139:Receptor, Angiotensin, Type 2; D012964:Sodium; D043384:Glutamyl Aminopeptidase; D006152:Cyclic GMP
keywords: aminopeptidase A; hypertension; ob/ob mice; obesity; renin-angiotensin-aldosterone system