Assessing the Relationship of Angiotensin II Type 1 Receptors with Erythropoietin in a Human Model of Endogenous Angiotensin II Type 1 Receptor Antagonism

作者：Calo Lorenzo A^*; Davis Paul A; Maiolino Giuseppe; Pagnin Elisa; Ravarotto Verdiana; Naso Elena; Carraro Gianni; Naso Agostino

来源：CardioRenal Medicine, 2016, 6(1): 16-24.

DOI：10.1159/000439183

• Angiotensin II
• Angiotensin II receptors
• Erythropoietin
• NOX4
• Nitric oxide
• Heme oxygenase-1

Hypothesis/Introduction: 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. Materials and 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/I; 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.

• 出版日期2016