title: The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension.
abstract: BACKGROUND
  Hypotension in septic patients results from hypovolemia, vasodilatation and hyporeactivity to vasoconstrictors, such as angiotensin II. The AT1 receptor-associated protein 1 (Arap1) is expressed in vascular smooth muscle cells and increases the surface expression of the AT1-receptor in vitro. We hypothesized that dysregulation of Arap1 may contribute to vascular hyporeactivity to angiotensin II during endotoxemia.
  
  
  METHODS
  Arap1-deficient mice were used to assess the role of Arap1 in sepsis-induced hypotension. The isolated perfused kidney was used as an in vitro model to determine the relevance of Arap1 for vascular resistance and sensitivity to angiotensin II.
  
  
  RESULTS
  During endotoxemia, mean arterial blood pressure (MAP) decreased in both genotypes, with the time course of sepsis-induced hypotension being markedly accelerated in Arap1-/- compared to +/+ mice. However, baseline MAP was similar in Arap1-/- and wildtype mice (102 ± 2 vs.103 ± 2 mmHg; telemetry measurements; n = 10; P = 0.66). Following lipopolysaccharide (LPS) injections (3 mg/kg), Arap1 expression was successively down-regulated in the wildtype mice, reaching levels below 10% of baseline expression. The endotoxemia-related decline in Arap1 expression could be recapitulated in cultured mesangial cells by incubation with pro-inflammatory cytokines, such as tumor necrosis factor α and interferon γ. Plasma renin concentration was increased in Arap1-/- mice compared to wildtype mice (66 ± 6 vs. 41 ± 4 ng AngI/ml/h; n = 23; P = 0.001), presumably contributing to preserved MAP under baseline conditions. The sensitivity of the vasculature to angiotensin II was reduced in Arap1-/- compared to +/+ mice, as determined in the isolated perfused kidney.
  
  
  CONCLUSIONS
  Our data suggest that down-regulation of Arap1 expression during sepsis contributes to the development of hypotension by causing reduced vascular sensitivity to angiotensin II.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mederle
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
authors.forename: Veronika
authors.initials: V
authors.lastname: Kattler
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Doblinger
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Klaus
authors.initials: K
authors.lastname: Höcherl
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Hayo
authors.initials: H
authors.lastname: Castrop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D015536:Down-Regulation; D007022:Hypotension / Q000209:etiology* / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D018805:Sepsis / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D008070:Lipopolysaccharides; D012083:Renin