Na<sup>+</sup>/K<sup>+</sup>-ATPase Alpha 2 Isoform Elicits Rac1-Dependent Oxidative Stress and TLR4-Induced Inflammation in the Hypothalamic Paraventricular Nucleus in High Salt-Induced Hypertension
Qing Su,
Xiao-Jing Yu,
Xiao-Min Wang,
Bo Peng,
Juan Bai,
Hong-Bao Li,
Ying Li,
Wen-Jie Xia,
Li-Yan Fu,
Kai-Li Liu,
Jin-Jun Liu,
Yu-Ming Kang
Affiliations
Qing Su
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Xiao-Jing Yu
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Xiao-Min Wang
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Bo Peng
School of Clinical Medicine, Xi’an Jiaotong University, Xi’an 710061, China
Juan Bai
Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
Hong-Bao Li
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Ying Li
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Wen-Jie Xia
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Li-Yan Fu
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Kai-Li Liu
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Jin-Jun Liu
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Yu-Ming Kang
Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Shaanxi Engineering and Research Center of Vaccine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China
Background: Numerous studies have indicated that a high salt diet inhibits brain Na+/K+-ATPase (NKA) activity, and affects oxidative stress and inflammation in the paraventricular nucleus (PVN). Furthermore, Na+/K+-ATPase alpha 2-isoform (NKA α2) may be a target in the brain, taking part in the development of salt-dependent hypertension. Therefore, we hypothesized that NKA α2 regulates oxidative stress and inflammation in the PVN in the context of salt-induced hypertension. Methods: Part I: We assessed NKA subunits (NKA α1, NKA α2, and NKA α3), Na+/K+-ATPase activity, oxidative stress, and inflammation in a high salt group (8% NaCl) and normal salt group (0.3% NaCl). Part II: NKA α2 short hairpin RNA (shRNA) was bilaterally microinjected into the PVN of salt-induced hypertensive rats to knockdown NKA α2, and we explored whether NKA α2 regulates downstream signaling pathways related to protein kinase C γ (PKC γ)-dependent oxidative stress and toll-like receptor 4 (TLR4)-induced inflammation in the PVN to promote the development of hypertension. Results: High salt diet increased NKA α1 and NKA α2 protein expression in the PVN but had no effect on NKA α3 compared to the normal salt diet. Na+/K+-ATPase activity and ADP/ATP ratio was lower, but NAD(P)H activity and NF-κB activity in the PVN were higher after a high salt diet. Bilateral PVN microinjection of NKA α2 shRNA not only improved Na+/K+-ATPase activity and ADP/ATP ratio but also suppressed PKC γ-dependent oxidative stress and TLR4-dependent inflammation in the PVN, thus decreasing sympathetic activity in rats with salt-induced hypertension. Conclusions: NKA α2 in the PVN elicits PKC γ/Rac1/NAD (P)H-dependent oxidative stress and TLR4/MyD88/NF-κB-induced inflammation in the PVN, thus increasing MAP and sympathetic activity during the development of salt-induced hypertension.
