title: Reduced plasma angiotensin II levels are reversed by hydroxyurea treatment in mice with sickle cell disease.
abstract: OBJECTIVE
  Sickle cell disease (SCD) pathogenesis leads to recurrent vaso-occlusive and hemolytic processes, causing numerous clinical complications including renal damage. As vasoconstrictive mechanisms may be enhanced in SCD, due to endothelial dysfunction and vasoactive protein production, we aimed to determine whether the expression of proteins of the renin-angiotensin system (RAS) may be altered in an animal model of SCD.
  
  
  METHODS
  Plasma angiotensin II (Ang II) was measured in C57BL/6 (WT) mice and mice with SCD by ELISA, while quantitative PCR was used to compare the expressions of the genes encoding the angiotensin-II-receptors 1 and 2 (AT1R and AT2R) and the angiotensin-converting enzymes (ACE1 and ACE2) in the kidneys, hearts, livers and brains of mice. The effects of hydroxyurea (HU; 50-75mg/kg/day, 4weeks) treatment on these parameters were also determined.
  
  
  RESULTS
  Plasma Ang II was significantly diminished in SCD mice, compared with WT mice, in association with decreased AT1R and ACE1 expressions in SCD mice kidneys. Treatment of SCD mice with HU reduced leukocyte and platelet counts and increased plasma Ang II to levels similar to those of WT mice. HU also increased AT1R and ACE2 gene expression in the kidney and heart.
  
  
  CONCLUSIONS
  Results indicate an imbalanced RAS in an SCD mouse model; HU therapy may be able to restore some RAS parameters in these mice. Further investigations regarding Ang II production and the RAS in human SCD may be warranted, as such changes may reflect or contribute to renal damage and alterations in blood pressure.
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Alisson F
authors.initials: AF
authors.lastname: dos Santos
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Camila B
authors.initials: CB
authors.lastname: Almeida
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Ana F
authors.initials: AF
authors.lastname: Brugnerotto
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Roversi
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Flávia R
authors.initials: FR
authors.lastname: Pallis
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Carla F
authors.initials: CF
authors.lastname: Franco-Penteado
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lanaro
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Dulcinéia M
authors.initials: DM
authors.lastname: Albuquerque
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Flávia C
authors.initials: FC
authors.lastname: Leonardo
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.affiliation: INCT de Sangue, Hematology and Hemotherapy Center, School of Medicine, University of Campinas -UNICAMP, Campinas, Sao Paulo, Brazil. Electronic address: conran@unicamp.br.
authors.forename: Nicola
authors.initials: N
authors.lastname: Conran
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000503:physiopathology; D000804:Angiotensin II / Q000097:blood*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006918:Hydroxyurea / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D006918:Hydroxyurea
keywords: Angiotensin II; Kidneys; Renin–angiotensin system; Sickle cell disease; Vasoconstriction