title: Assessing the Relationship of Angiotensin II Type 1 Receptors with Erythropoietin in a Human Model of Endogenous Angiotensin II Type 1 Receptor Antagonism.
abstract: OBJECTIVE
  Angiotensin II (Ang II) has been shown to control erythropoietin (EPO) synthesis as Ang II type 1 receptor (AT1R) blockers block Ang-II-induced EPO oversecretion. To further explore the involvement of AT1R in processes controlling EPO levels, plasma EPO and mononuclear cell NADPH oxidase 4 (NOX4) - a NOX family member involved in oxygen sensing, which is a process central to controlling EPO levels - were assessed in Bartter's/Gitelman's syndrome (BS/GS) patients, a human model of endogenous AT1R antagonism and healthy subjects. Heme oxygenase (HO)-1, antioxidant and anti-inflammatory factor related to NOX4 activation, and the relationship of EPO and NOX4 to HO-1 were also assessed.
  
  
  METHODS
  EPO was measured by chemiluminescent immunoassay, HO-1 by sandwich immunoassay and NOX4 protein expression by Western blot.
  
  
  RESULTS
  EPO was increased in BS/GS patients compared to healthy subjects (7.64 ± 2.47 vs. 5.23 ± 1.07 U/l; p = 0.025), whereas NOX4 did not differ between BS/GS and healthy subjects (1.76 ± 0.61 vs. 1.65 ± 0.54 densitometric units; p = n.s.), and HO-1 was increased in BS/GS patients compared to healthy subjects (9.58 ± 3.07 vs. 5.49 ± 1.04 ng/ml; p = 0.003). NOX4 positively correlated with HO-1 only in BS/GS patients; no correlation was found between EPO and either NOX4 or HO-1 in those two groups.
  
  
  CONCLUSIONS
  The effect of the renin-angiotensin system on EPO cannot be solely mediated by Ang II via AT1R signaling, but rather, EPO levels are also determined by a complex interrelated set of signals that involve AT2R, nitric oxide levels, NOX4 and HO-1 activity.
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Calò
authors.affiliation: Department of Nutrition, University of California, Davis, Calif., USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davis
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maiolino
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Verdiana
authors.initials: V
authors.lastname: Ravarotto
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Naso
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Carraro
authors.affiliation: Department of Medicine, Nephrology and Hypertension, University of Padova, Padova, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Naso
keywords: Angiotensin II; Angiotensin II receptors; Erythropoietin; Heme oxygenase-1; NOX4; Nitric oxide