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Genistein Alleviates Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus by Activating the Sirt1/Nrf2 Pathway in High Salt-Induced Hypertension

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Abstract

Hypertension caused by a high-salt (HS) diet is one of the major causes of cardiovascular diseases. Underlining pathology includes oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN). This study investigates genistein’s (Gen) role in HS-induced hypertension and the underlying molecular mechanism. We placed male Wistar rats on HS (8% NaCl) or normal salt diet (0.3% NaCl). Then, we injected bilateral PVN in rats with Gen, vehicle, or nicotinamide (NAM) for 4 weeks. Tail cuff was used weekly to assess the systolic pressure, diastolic pressure, and mean arterial pressure (MAP). Cardiac hypertrophy was analyzed by heart weight/body weight ratio and wheat germ agglutinin staining. ELISA kits, Western blot, or dihydroethidium staining determined the levels of inflammatory cytokines and oxidative stress markers. Western blot measured protein levels of Sirt1, Ac-FOXO1, Nrf2, NQO-1, HO-1, and gp91phox. Our result showed that PVN infusion of Gen significantly reduced the increase of systolic pressure, diastolic pressure, and MAP induced by an HS diet. Additionally, there was a decrease in cardiac hypertrophy and the levels of inflammatory cytokines in PVN and plasma. Meanwhile, PVN infusion of Gen notably inhibited the levels of oxidized glutathione and superoxide dismutase and improved the glutathione level and total antioxidant capacities and superoxide dismutase activities. It also decreased the level of reactive oxygen species and gp91phox expression in PVN. Furthermore, Gen infusion markedly increases the Sirt1, Nrf2, HO-1, and NQO-1 levels and decreases the Ac-FOXO1 level. However, PVN infusion of NAM could significantly block these changes induced by Gen in HS diet rats. Our results demonstrated that PVN infusion of Gen could inhibit the progression of hypertension induced by an HS diet by activating the Sirt1/Nrf2 pathway.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by grants Shaanxi Key Research and Development Program (No.2021SF-203), the National Natural Science Foundation of China (No.81800373), and the Natural Science Research Program of Shaanxi Province (Nos. 2020JM-079, 2020GCZX-13 and 2019JQ-263).

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Author notes

  1. Li-Gang Niu, Na Sun, and Kai-Li Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi’an, 710061, China

    Li-Gang Niu, Kai-Li Liu, Qing Su, Jie Qi, Li-Yan Fu, Guo-Rui Xin & Yu-Ming Kang

  2. Department of Breast Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Li-Gang Niu

  3. Department of Physiology, Xi’an Medical University, Xi’an, 710021, China

    Na Sun

  4. Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Yu-Ming Kang

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Contributions

LGN, NS, and YMK designed the study. LGN, NS, KLL, QS, and JQ performed all experiments and drafted the manuscript. YLF and QS also performed the data analysis and drafted the manuscript. GRX participated in data analysis. NS, KLL, and JQ critically revised the manuscript. LGN and YMK edited the revised manuscript language. All authors reviewed the final manuscript.

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Correspondence to Yu-Ming Kang.

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Niu, LG., Sun, N., Liu, KL. et al. Genistein Alleviates Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus by Activating the Sirt1/Nrf2 Pathway in High Salt-Induced Hypertension. Cardiovasc Toxicol 22, 898–909 (2022). https://doi.org/10.1007/s12012-022-09765-3

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