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. 2021 Mar 4:15:642015.
doi: 10.3389/fnins.2021.642015. eCollection 2021.

Paraventricular Nucleus Infusion of Oligomeric Proantho Cyanidins Improves Renovascular Hypertension

Xiao-Jing Yu  1 , Guo-Rui Xin  1 , Kai-Li Liu  1 , Xiao-Jing Liu  2 , Li-Yan Fu  1 , Jie Qi  1 , Kai B Kang  3 , Ting-Ting Meng  1 , Qiu-Yue Yi  4 , Ying Li  1 , Yao-Jun Sun  5 , Yu-Ming Kang  1
Affiliations

Paraventricular Nucleus Infusion of Oligomeric Proantho Cyanidins Improves Renovascular Hypertension

Xiao-Jing Yu et al. Front Neurosci. .

Abstract

Oxidative stress plays an important role in the pathogenesis of hypertension. Oligomeric proantho cyanidins (OPC) is the main polyphenol presents in grape seed and is known for its potent antioxidant and anti-inflammatory properties. In the present study, we hypothesize that OPC can attenuate oxidative stress in the paraventricular nucleus of hypothalamus (PVN), ameliorate neurotransmitter imbalance, decrease the blood pressure and sympathetic activity in renovascular hypertensive rats. After induction of renovascular hypertension by the two-kidney one-clip (2K-1C) method, male Sprague-Dawley rats received chronic bilateral PVN infusion of OPC (20 μg/h) or vehicle via osmotic minipump for 4 weeks. We found that hypertension induced by 2K-1C was associated with the production of reactive oxygen species (ROS) in the PVN. Infusion of OPC in the PVN significantly reduced the systolic blood pressure and norepinephrine in plasma of 2K-1C rats. In addition, PVN infusion of OPC decreased the level of ROS and the expression of stress-related nicotinamide adenine dinucleotide phosphate (NADPH) oxidases subunit NOX4, increased the levels of nuclear factor E2-related factor 2 (Nrf2) and antioxidant enzyme, balanced the content of cytokines, increased expression of glutamic acid decarboxylase and decreased the expression of tyrosine hydroxylase in the PVN of 2K-1C rats. Our findings provided strong evidence that PVN infusion of OPC inhibited the progression of renovascular hypertension through its potent anti-oxidative and anti-inflammatory function in the PVN.

Keywords: hypertension; hypothalamic paraventricular nucleus; neurotransmitters; oligomeric proantho cyanidins; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Effects of OPC on SBP. 2K-1C induced significant increase in the SBP, which was reduced by bilateral PVN infusions of OPC. Data are mean ± SEM. ∗P < 0.05 versus control rats (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group. C1, three days before the experiment.
FIGURE 2
FIGURE 2
Effects of OPC on levels of NE in the plasma of rats. 2K-1C induced higher level of NE in the plasma than that of SHAM ones, and PVN infusions of OPC alleviated NE elevation in the PVN of the 2K-1C rats. Data are mean ± SEM. ∗P < 0.05 versus control rats (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
FIGURE 3
FIGURE 3
Effects of OPC on protein expression of Nrf2 in the PVN. (A) Western blotting results of Nrf2 and β-actin expression; (B) Statistical results of Nrf2 expression; Data are normalized to β-actin and shown as mean ± SEM. ∗P < 0.05 versus control group (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
FIGURE 4
FIGURE 4
Effects of PVN infusion of OPC on DHE in the PVN of 2K-1C rats. (A) The DHE displayed superoxide anion production (red fluorescence) in the PVN; (B) Relative fluorescence intensity of DHE in the PVN. Data are mean ± SEM. ∗P < 0.05 versus control group (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
FIGURE 5
FIGURE 5
Effects of PVN infusion of OPC on Cu/Zn SOD in the PVN of 2K-1C rats. (A) Western blotting results of Cu/Zn-SOD and β-actin expression; (B) Statistical results of Cu/Zn-SOD expression; Data are modified by β-actin and shown as mean ± SEM. ∗P < 0.05 versus control group (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
FIGURE 6
FIGURE 6
Effects of OPC on NOX4 in the PVN of 2K-1C rats. (A) Immunofluorescent staining of NOX4 (red fluorescence) in the PVN; (B) The number of NOX4 positive neurons per 1 × 104 μm2; (C) Western blotting results of NOX4; (D) Statistical results of NOX4 expression. Data are mean ± SEM. ∗P < 0.05 versus control group (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6/group.
FIGURE 7
FIGURE 7
Effects of PVN infusion of OPC on IL-10 and IL-1β in the PVN of 2K-1C rats. (A) Immunofluorescent staining of IL-1β (red fluorescence, × 400) and Immunohistochemical staining of IL-10 (brown) in the PVN; (B) The number of IL-1β and IL-10 positive neurons per 1 × 104 μm2; (C) Top: Roles of OPC on the expression of IL-1β; Bottom: Effects of OPC on the expression of IL-10. Data are mean ± SEM. *P < 0.05 versus control rats (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
FIGURE 8
FIGURE 8
Effects of PVN infusion of OPC on neuronal activity in 2K-1C rats. (A) Immunohistochemical analysis about the expression of Fra-LI in the PVN; (B) The number of Fra-LI positive neurons per 1 × 104 μm2. Data are mean ± SEM. ∗P < 0.05 versus control group (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
FIGURE 9
FIGURE 9
Effects of PVN infusion of OPC on expression of TH and GAD67 in the PVN. (A) Western blotting results of TH and GAD67 expressions in the PVN; (B) Statistical results of TH and GAD67 expression in the PVN; (C) Immunofluorescence staining of TH (red fluorescence) in the PVN; (D) the number of TH positive neurons per 1 × 104 μm2. Data are normalized to β-actin and shown as mean ± SEM. ∗P < 0.05 versus control group (SHAM + PVN aCSF or SHAM + PVN OPC); †P < 0.05 versus 2K-1C + PVN aCSF. n = 6 per group.
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