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

• Published in: Cardiovascular toxicology 2021-06, Vol.21 (6), p.472-489
• Main Authors: Li, Ying, Yu, Xiao-Jing, Xiao, Tong, Chi, Hong-Li, Zhu, Guo-Qing, Kang, Yu-Ming
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antioxidants; Autophagy; Biomedical and Life Sciences; Biomedicine; Blood Pressure; Brain; Cardiology; Chemical synthesis; Cytochrome; Cytochrome c; Cytochrome-c oxidase; Cytochromes; Disease Models, Animal; Down-regulation; Electron transport; Gene Knockdown Techniques; Genetic aspects; Genetic transcription; Glutathione; Hypertension; Hypertension, Renovascular - genetics; Hypertension, Renovascular - metabolism; Hypertension, Renovascular - physiopathology; Hypertension, Renovascular - prevention & control; Hypothalamus; Kidneys; Male; Membrane potential; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Myosin; NAD; Norepinephrine; Nuclear Respiratory Factor 1 - genetics; Nuclear Respiratory Factor 1 - metabolism; Nuclei (cytology); Oxidases; Oxidative Stress; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular Hypothalamic Nucleus - physiopathology; Paraventricular nucleus; Peroxiredoxin; Phagocytosis; Pharmacology/Toxicology; Quinone oxidoreductase; Quinones; Rats; Rats, Sprague-Dawley; RNA Interference; Superoxide; Superoxide dismutase; Superoxides - metabolism; Thioredoxin
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-021-09641-6

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.