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. 2020 May 22:2020:8387654.
doi: 10.1155/2020/8387654. eCollection 2020.

High Concentrations of Uric Acid and Angiotensin II Act Additively to Produce Endothelial Injury

Quan Hong  1 , Liyuan Wang  1   2 , Zhiyong Huang  1   3 , Zhe Feng  1 , Shaoyuan Cui  1 , Bo Fu  1 , Guangyan Cai  1 , Xiangmei Chen  1 , Di Wu  1
Affiliations

High Concentrations of Uric Acid and Angiotensin II Act Additively to Produce Endothelial Injury

Quan Hong et al. Mediators Inflamm. .

Abstract

Renin angiotensin (Ang) system (RAS) activation in metabolic syndrome (MS) patients is associated with elevated uric acid (UA) levels, resulting in endothelial system dysfunction. Our previous study demonstrated that excessive UA could cause endothelial injury through the aldose reductase (AR) pathway. This study is the first to show that a high concentration of Ang II in human umbilical vein endothelial cells (HUVECs) increases reactive oxygen species (ROS) components, including O2 ·- and H2O2, and further aggravates endothelial system injury induced by high UA (HUA). In a MS/hyperuricemia model, nitric oxide (NO) production was decreased, followed by a decrease in total antioxidant capacity (TAC), and the concentration of the endothelial injury marker von Willebrand factor (vWF) in the serum was increased. Treatment with catalase and polyethylene glycol covalently linked to superoxide dismutase (PEG-SOD) to individually remove H2O2 and O2 ·- or treatment with the AR inhibitor epalrestat decreased ROS and H2O2, increased NO levels and TAC, and reduced vWF release. Taken together, these data indicate that HUA and Ang II act additively to cause endothelial dysfunction via oxidative stress, and specific elimination of O2 ·- and H2O2 improves endothelial function. We provide theoretical evidence to prevent or delay endothelial injury caused by metabolic diseases.

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Conflict of interest statement

The authors declare that they have no competing financial interests.

Figures

Figure 1
Figure 1
UA and Ang II induce endothelial injury. (a) The NO level of the supernatant was assayed by NO reduction. HUVECs were treated with 600 μmol/L UA (HUA), 10−7 mol/L Ang II (Ang II), or 600 μmol/L UA together with 10−7 mol/L Ang II (HUA+Ang II) to reduce NO production after 24 h of stimulation; ∗p < 0.05 compared to the normal control. The NO level in the HUA+Ang II group was significantly lower than that in the HUA group or the Ang II group; #p < 0.05 compared to the Ang II group; △p < 0.05 compared to the HUA group. (b) Western blotting was used to detect eNOS expression levels in HUVECs. The HUA, Ang II, and HUA+Ang II groups showed decreased phosphorated eNOS-ser1177 protein expression levels in HUVECs after 24 h of stimulation; ∗p < 0.05 compared to the normal control group. The phosphorated eNOS-ser1177 protein expression level in the HUA+Ang II group was significantly lower than that in the HUA group or the Ang II group; #p < 0.05 compared to the Ang II group; △p < 0.05 compared to the HUA group. (c–f) The vWF, ET1, IL-1β, and IL-18 concentration of the supernatant was assayed. HUA and Ang II increased vWF, ET1, IL-1β, and IL-18 production after 24 h of stimulation; ∗p < 0.05 compared to the normal control. The vWF, ET1, IL-1β, and IL-18 in the HUA+Ang II group were remarkably higher than those in the HUA group or the Ang II group; #p < 0.05 compared to the Ang II group; △p < 0.05 compared to the HUA group.
Figure 2
Figure 2
Total ROS production and ROS component generation in HUVECs induced by HUA or Ang II. HUVECs were cultured in confocal dishes and treated with 600 μmol/L UA (HUA) or 10−7 mol/L Ang II (Ang II) for 24 h. Then, cells were stained using ROS probes. (a) Compared to the control group, the HUA, Ang II, and HUA+Ang II groups generated more total intracellular ROS (∗p < 0.05), and no difference was observed between the HUA+Ang II group and the HUA or Ang II group (p > 0.05). (b) The HUA, Ang II, and HUA+Ang II groups showed remarkably increased H2O2 production compared to the control group (∗p < 0.05), and HUA+Ang II treatment increased H2O2 generation compared to individual treatment with HUA or Ang II (#p < 0.05 compared to the HUA group; △p < 0.05 compared to the Ang II group). (c) The HUA, Ang II, and HUA+Ang II groups showed remarkably higher O2·- production than the control group (∗p < 0.05), and HUA+Ang II treatment increased O2·- generation compared to individual treatment with HUA or Ang II (#p < 0.05 compared to the HUA group). (d) The 1O2 level was increased in the Ang II group (∗p < 0.05) and decreased in the HUA group compared to that in the control group (∗p < 0.05). The 1O2 level was lower in the HUA+Ang II group than that in the Ang II group (#p < 0.05); (e) the ·OH level was higher in the HUA, Ang II, and HUA+Ang II groups than that in the control group (∗p < 0.05) and was significantly higher in the HUA+Ang II group than that in the HUA and Ang II groups (#p < 0.01 compared to the HUA group; △p < 0.01 compared to the Ang II group). (f) The ONOO− level was higher in the HUA, Ang II, and HUA+Ang II groups than that in the control group (∗p < 0.05) and was significantly higher in the HUA+Ang II group compared to that in the HUA or Ang II group (#p < 0.01 compared to the HUA group; △p < 0.01 compared to the Ang II group).
Figure 3
Figure 3
NOX expression in HUVECs induced by HUA or Ang II. (a, b) NOX2 and NOX4 protein expressions were assayed by Western blot. The HUA, Ang II, and HUA+Ang II groups showed increased NOX4 protein expression levels in HUVECs after 24 h of stimulation; ∗p < 0.05 compared to the normal control group, but there is no difference of NOX2 expression between each group. The NOX4 protein expression level in the HUA+Ang II group was significantly higher than that in the HUA group or the Ang II group; #p < 0.05 compared to the Ang II group; △p < 0.05 compared to the HUA group. (c) Also, NOX activity in HUA, Ang II, and HUA+Ang II groups increased remarkably when compared with normal control. Particularly, that was significantly higher in the HUA+Ang II group compared to that in the HUA or Ang II group; #p < 0.05 compared to the Ang II group; △p < 0.05 compared to the HUA group.
Figure 4
Figure 4
Body weight, systolic blood pressure, IGTT, and serum of Ang II of animals. (a) The body weight of animals in each group increased before 5 weeks of age and decreased after 8 weeks of age. No difference was observed among the groups (p > 0.05). (b) The systolic blood pressure increased to 200 mmHg at 4 weeks and maintained a steady state. No difference was observed among the groups (p > 0.05). (c) Intraperitoneal glucose tolerance of animals in each group has no differences, p > 0.05. (d) Serum Ang II level increased significantly in the HUA animal model, but catalase, PEG-SOD, and epalrestat did not decrease the Ang II concentration; there was no differences between the treatment groups and the HUA group, p > 0.05.
Figure 5
Figure 5
ROS scavenging improves endothelial function in the MS model. SHR rats were fed a high-fat and high-glucose diet and administered oxonic acid (250 mg kg−1 d−1) and UA (250 mg kg−1 d−1) via intraperitoneal injection to generate a model of MS associated with hyperuricemia. (a) In the HUA group, the serum NO level was significantly decreased compared to that in the SHR group (p < 0.05). After administration of catalase, PEG-SOD, or epalrestat, the serum NO level of HUA rats increased remarkably. (b) Compared to the H2O2 level in SHR rats, the H2O2 level in MS model rats was significantly increased (p < 0.05), and treatment with catalase, PEG-SOD, or epalrestat decreased H2O2 generation (p < 0.05). (c) Compared to the TAC of SHR rats, the TAC of MS model rats was significantly decreased (p < 0.05); treatment with and catalase, PEG-SOD, or epalrestat increased H2O2 generation (p < 0.05). (d) vWF and (e) ET1 are two markers of endothelial injury. In the HUA group, the serum vWF and ET1 concentration was significantly increased compared to that in the SHR group (p < 0.05). After administration of catalase, PEG-SOD, or epalrestat, the serum vWF and ET1 concentration in HUA rats increased remarkably (p < 0.05).
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