Na+/K+-ATPase Alpha 2 Isoform Elicits Rac1-Dependent Oxidative Stress and TLR4-Induced Inflammation in the Hypothalamic Paraventricular Nucleus in High Salt-Induced Hypertension

Abstract

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.

Dexmedetomidine Attenuates Lipopolysaccharide-Induced Sympathetic Activation and Sepsis via Suppressing Superoxide Signaling in Paraventricular Nucleus

“…Microinjection of yohimbine to block α2R or DETC to increase superoxide levels in the PVN almost abolished the roles of intravenous administration of DEX in inhibiting LPS-induced changes in RSNA, MAP and HR ( Figure 7 D). It is known that oxidative stress and inflammation in the PVN increase sympathetic outflow [ 16 , 46 ]. The present study has shown that NADPH oxidase-derived superoxide production in the PVN mediates the inhibitory effects of DEX on sympathetic activity as we described above.…”

Resveratrol in the Hypothalamic Paraventricular Nucleus Attenuates Hypertension by Regulation of ROS and Neurotransmitters

“…SOD1 is an important antioxidant enzyme which inhibits ROS production [ 32 ]. Some studies have shown that elevated NOX activity and ROS production in the PVN stimulates abnormal peripheral SNA in high-salt or Ang II-induced hypertension rats [ 38 , 41 ]. Blocking the excessive production of ROS in PVN can inhibit SNA in hypertensive rats [ 40 ].…”

“…Researchers have also found that NF-κB activities in the PVN are closely associated with the intensity of SNA in hypertensive rats [ 24 , 47 ]. NF-κB and oxidative stress in PVN play crucial roles in the pathogenesis of hypertension [ 38 , 48 ]. SIRT1 can directly act on NF-κB and reduce the acetylation level of p65 subunit Lys 310 , thereby inhibiting the transcription activity of NF-κB [ 49 ].…”

“…Animals were anesthetized with isoflurane at the end of 28th day. Plasma specimens and brain tissue were collected and stored at −80 °C for future analysis [ 38 ].…”

Progress of Research into the Interleukin-1 Family in Cardiovascular Disease

“… 31 , 94 IL-38 inhibited human adipocyte differentiation and reduced secretion of inflammatory cytokines, IL-1β and MCP-1, 95 and IL-38 reduction of joint inflammation involved the NF-κB signaling pathway also known to be involved in hypertension. 96 , 97 Macrophages, smooth muscle cells and vascular endothelial cells also release IL-38 under apoptotic conditions and affect the circulatory Bcl-2/Bax/Caspase-3 signaling pathway, attenuating hyperlipidemia. 68 , 94 No direct relationship between IL-38 and hypertension has yet been shown but this molecule does seem to ameliorate the disorder ( Figure 2 ).…”