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Nrf1 Knock-Down in the Hypothalamic Paraventricular Nucleus Alleviates Hypertension Through Intervention of Superoxide Production-Removal Balance and Mitochondrial Function

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Abstract

Oxidative stress in the hypothalamic paraventricular nucleus (PVN) contributes greatly to the development of hypertension. The recombinant nuclear respiratory factor 1 (Nrf1) regulates the transcription of several genes related to mitochondrial respiratory chain function or antioxidant expression, and thus may be involved in the pathogenesis of hypertension. Here we show that in the two-kidney, one-clip (2K1C) hypertensive rats the transcription level of Nrf1 was elevated comparing to the normotensive controls. Knocking down of Nrf1 in the PVN of 2K1C rats can significantly reduce their blood pressure and level of plasma norepinephrine (NE). Analysis revealed significant reduction of superoxide production level in both whole cell and mitochondria, along with up-regulation of superoxide dismutase 1 (Cu/Zn-SOD), NAD(P)H: quinone oxidoreductase 1 (NQO1), thioredoxin-dependent peroxiredoxin 3 (Prdx3), cytochrome c (Cyt-c) and glutathione synthesis rate-limiting enzyme (glutamyl-cysteine ligase catalytic subunit (Gclc) and modifier subunit (Gclm)), and down-regulation of cytochrome c oxidase subunit VI c (Cox6c) transcription after Nrf1 knock-down. In addition, the reduced ATP production and elevated mitochondrial membrane potential in the PVN of 2K1C rats were reinstated with Nrf1 knock-down, together with restored expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (Tfam), coiled-coil myosin-like BCL2-interacting protein (Beclin1), and Mitofusin 1 (Mfn1), which are related to the mitochondrial biogenesis, fusion, and autophagy. Together, the results indicate that the PVN Nrf1 is associated with the development of 2K1C-induced hypertension, and Nrf1 knock-down in the PVN can alleviate hypertension through intervention of mitochondrial function and restorement of the production-removal balance of superoxide.

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Data Availability

The data are available upon request to the corresponding authors.

Abbreviations

2K1C:

Two-kidney, one-clip

AAV:

Adeno-associated virus

Beclin1 :

Coiled-coil myosin-like BCL2-interacting protein

CNC-bZIP:

Cap-n-collar subfamily of basic leucine zipper

Cox2 :

Mitochondrial-encoded subunit II

Cox6c :

Cytochrome c oxidase subunit VI c

Cu/Zn-SOD:

Cu/Zn superoxide dismutase, superoxide dismutase 1

Cyt-c :

Cytochrome c

DHE:

Dihydroethidium

Drp1 :

Cytosolic GTPase dynamin-related protein 1

Elisa:

Enzyme linked immunosorbent assay

Gclc :

Glutamyl-cysteine ligase catalytic subunit

Gclm :

Glutamyl-cysteine ligase modifier subunit

GSH:

Glutathione

HE staining:

Hematoxylin–eosin staining

IL-10:

Interleukin-10

IL-1β:

Interleukin-1 beta

Mfn1/2 :

Mitofusin 1/2

Miro1 :

Mitochondrial rho GTPase 1

mtDNA:

Mitochondrial DNA

NE:

Norepinephrine

NQO1 :

NAD(P)H: quinone oxidoreductase 1

Nrf1 :

Recombinant nuclear respiratory factor 1

Nrf2 :

Nuclear respiratory factor 2

PGC-1α :

Peroxisome proliferator-activated receptor-γ coactivator 1α

PIC:

Pro-inflammatory cytokine

PMSF:

Phenylmethanesulfonyl fluoride

Prdx3 :

Thioredoxin-dependent peroxiredoxin 3

PVN:

Hypothalamic paraventricular nucleus

ROS:

Reactive oxygen species

RT-qPCR:

Reverse transcript quantitative-polymerase chain reaction

SBP:

Systolic blood pressure

SD:

Sprague–Dawley

SHR:

Spontaneously hypertensive rats

Tfam :

Mitochondrial transcription factor A

Vdac1 :

Voltage-dependent anion-selective channel protein 1

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Funding

This study was supported by National Natural Science Foundation of China (Grant Nos. 81800372, 81770426), China Postdoctoral Science Foundation (Grant No. 2017M620457) and the Shaanxi Natural Science Foundation (Grant Nos. 2018JQ8016, 2019JQ-605).

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Authors and Affiliations

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

    Ying Li, Xiao-Jing Yu, Tong Xiao, Hong-Li Chi & Yu-Ming Kang

  2. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, 210029, China

    Guo-Qing Zhu

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Contributions

YL, X-JY and Y-MK contributed to the study conception and design, YL, TX and H-LC performed the experiment and collected the data, YL and TX analyzed the data, YL wrote the first draft of the manuscript and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yu-Ming Kang.

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Li, Y., Yu, XJ., Xiao, T. et al. Nrf1 Knock-Down in the Hypothalamic Paraventricular Nucleus Alleviates Hypertension Through Intervention of Superoxide Production-Removal Balance and Mitochondrial Function. Cardiovasc Toxicol 21, 472–489 (2021). https://doi.org/10.1007/s12012-021-09641-6

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