NADPH Oxidase Activity and Reactive Oxygen Species Production in Brain and Kidney of Adult Male Hypertensive Ren-2 Transgenic Rats (original) (raw)
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American Journal of Nephrology, 2009
lation of MnSOD with little change in CuZnSOD. Conclusions: Chronic hypertension in phenol-injected rats is associated with upregulation of NAD(P)H oxidase and hence increased O 2-ؒ production capacity in the key regions of the brain involved in regulation of blood pressure. Since reactive oxygen species can intensify central noradrenergic activity, the observed maladaptive changes may contribute to the genesis and maintenance of the associated hypertension.
Hypertension, 2000
This study was designed to test the hypothesis that stimulation of nicotinamide adenine dinucleotide/ nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase is involved in increased vascular superoxide anion (⅐O 2 Ϫ) production in spontaneously hypertensive rats (SHR). The study was performed in 16-week-old and 30-week-old normotensive Wistar-Kyoto rats (WKY 16 and WKY 30 , respectively) and in 16-week-old and 30-week-old SHR (SHR 16 and SHR 30 , respectively). In addition, 16-week-old SHR were treated with oral irbesartan (average dose 20 mg/kg per day) for 14 weeks (SHR 30-I). Aortic NADH/NADPH oxidase activity was determined by use of chemiluminescence with lucigenin. The expression of p22phox messenger RNA was assessed by competitive reverse transcription-polymerase chain reaction. Vascular responses to acetylcholine were determined by isometric tension studies. Aortic wall structure was studied, determining the media thickness and the cross-sectional area by morphometric analysis. Whereas systolic blood pressure was significantly increased in the 2 groups of hypertensive animals compared with their normotensive controls, no differences were observed in systolic blood pressure between SHR 30 and SHR 16. No other differences in the parameters measured were found between WKY 16 and SHR 16. In SHR 30 compared with WKY 30 , we found significantly greater p22phox mRNA level, NADH/NADPH-driven ⅐O 2 Ϫ production, media thickness, and cross-sectional area and an impaired vasodilation in response to acetylcholine. Treated SHR had similar NADH/NADPH oxidase activity and p22phox expression as the WKY 30 group. The vascular functional and morphological parameters were improved in SHR 30-I. These findings suggest that an association exists between p22phox gene overexpression and NADH/NADPH overactivity in the aortas of adult SHR. Enhanced NADH/NADPH oxidase-dependent ⅐O 2 Ϫ production may contribute to endothelial dysfunction and vascular hypertrophy in this genetic model of hypertension.
Role of the NADPH Oxidases in the Subfornical Organ in Angiotensin II-Induced Hypertension
Hypertension, 2012
Reactive oxygen species and the NADPH oxidases contribute to hypertension via mechanisms that remain undefined. Reactive oxygen species produced in the central nervous system have been proposed to promote sympathetic outflow, inflammation, and hypertension, but the contribution of the NADPH oxidases to these processes in chronic hypertension is uncertain. We therefore sought to identify how NADPH oxidases in the subfornical organ (SFO) of the brain regulate blood pressure and vascular inflammation during sustained hypertension. We produced mice with loxP sites flanking the coding region of the NADPH oxidase docking subunit p22 phox . SFO-targeted injections of an adenovirus encoding cre-recombinase markedly diminished p22 phox , Nox2, and Nox4 mRNA in the SFO, as compared with a control adenovirus encoding red-fluorescent protein injection. Increased superoxide production in the SFO by chronic angiotensin II infusion (490 ng/kg min –1 ×2 weeks) was blunted in adenovirus encoding cre...
Age-dependent redox status in the brain stem of NO-deficient hypertensive rats
Journal of Biomedical Science
Background: The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors. Methods: Young (4 weeks) and adult (10 weeks) Wistar rats were treated with 7-nitroindazole (7-NI group, 10 mg/ kg/day), a specific nNOS inhibitor, with N G-nitro-L-arginine-methyl ester (L-NAME group, 50 mg/kg/day), a nonspecific NOS inhibitor, and with drinking water (Control group) during 6 weeks. Systolic blood pressure was measured by non-invasive plethysmography. Expression of genes (AT1R, AT2R, p22phox, SOD and NOS isoforms, HO-1, MDR1a, housekeeper GAPDH) was identified by real-time PCR. NOS activity was detected by conversion of [3H]-L-arginine to [3H]-L-citrulline and SOD activity was measured using UV VIS spectroscopy. Results: We observed a blood pressure elevation and decrease in NOS activity only after L-NAME application in both age groups. Gene expression of nNOS (youngs) and eNOS (adults) in the brain stem decreased after both inhibitors. The radical signaling pathway triggered by AT1R and p22phox was elevated in L-NAME adults, but not in young rats. Moreover, L-NAME-induced NOS inhibition increased antioxidant response, as indicated by the observed elevation of mRNA SOD3, HO-1, AT2R and MDR1a in adult rats. 7-NI did not have a significant effect on AT1R-NADPH oxidase-superoxide pathway, yet it affected antioxidant response of mRNA expression of SOD1 and stimulated total activity of SOD in young rats and mRNA expression of AT2R in adult rats. Conclusion: Our results show that chronic NOS inhibition by two different NOS inhibitors has age-dependent effect on radical signaling and antioxidant/detoxificant response in Wistar rats. While 7-NI had neuroprotective effect in the brain stem of young Wistar rats, L-NAME-induced NOS inhibition evoked activation of AT1R-NAD(P)H oxidase pathway in adult Wistar rats. Triggering of the radical pathway was followed by activation of protective compensation mechanism at the gene expression level.
2010
Reactive oxygen species in peripheral cardiovascular tissues are implicated in the pathogenesis of 2 kidney-1 clip hypertension. We recently identified an imbalance between reactive oxygen species generation and oxidant scavenging in the rostral ventrolateral medulla (RVLM) of 2 kidney-1 clip in rats. We tested whether enhanced superoxide signaling in RVLM of 2 kidney-1 clip rats contributes to the chronic hypertension via sympathetic activation in conscious rats. We enhanced superoxide scavenging in RVLM by overexpressing cytoplasmically targeted superoxide dismutase using an adenoviral vector (Ad-CMV-CuZnSOD) in Wistar rats (male, 150 to 180 g) in which the left renal artery was occluded partially 3 weeks earlier. Hypertension was documented using radiotelemetry recording of arterial pressure in conscious rats for 6 weeks. Renovascular hypertension elevated both serine phosphorylation of p47phox subunit of NADPH and superoxide levels in RVLM. The elevated superoxide levels were no...
American journal of …, 2009
Background Based on previous data, we hypothesized that an increase of angiotensin II (ang II)-via the ang II type 1 (aT-1) receptor-in the rostral ventrolateral medulla (RVLm) and the paraventricular nucleus (PVN) of the hypothalamus could activate NaD(P)H oxidase that will produce superoxides resulting in increased sympathetic activity and hypertension. Methods The mRNa expression of aT-1 receptors, NaD(P)H oxidase subunits (p47phox and gp91phox), and CuZnSOD were analyzed in the RVLm and PVN of male Wistar rats (Goldblatt hypertension model, 2K-1C). In addition, we administered Tempol 1 and 5 nmol into the RVLm, PVN, or systemically. The mean arterial pressure (maP) and renal sympathetic nerve activity (RSNa) were analyzed. results The aT-1 mRNa expression and NaD(P)H oxidase subunits was greater in the RVLm and PVN in 2K-1C compared to the control group. Furthermore, the CuZnSOD expression was similar in both groups. Tempol 1 nmol into the RVLm reduced maP (15 ± 1%) and RSNa (11 ± 2%) only in 2K-1C rats. Tempol (5 nmol) in the same region decreased the maP (12 ± 4%) and RSNa (20 ± 7%), respectively, only in 2K-1C. In the PVN, Tempol 5 nmol resulted in a significant fall in the maP (24 ± 1%) and in the RSNa (7.9 ± 2%) only in the 2K-1C. acute intravenous (IV) infusion of Tempol decreased maP and RSNa in the 2K-1C but not in the control rats. conclusions The data suggest that the hypertension and sympathoexcitation in 2K-1C rats were associated with an increase in oxidative stress within the RVLm, the PVN and systemically.
Journal of Hypertension, 2012
Objectives The rostral ventrolateral medulla (RVLM) of the brainstem and the paraventricular nucleus (PVN) of the hypothalamus play crucial roles in central cardiovascular regulation. In hypertensive rats, an imbalance of excitatory and inhibitory inputs to the RVLM enhances central sympathetic outflow. Increased reactive oxygen species (ROS) in the RVLM also contribute to sympathoexcitation, leading to hypertension. The aim of the present study was to elucidate whether ROS in the RVLM modulate synaptic transmission via excitatory and inhibitory amino acids and influence the excitatory inputs to the RVLM from the PVN in spontaneously hypertensive rats (SHRs). Methods and results We transfected adenovirus vectors encoding the manganese superoxide dismutase (AdMnSOD) gene to scavenge ROS in the RVLM both in Wistar-Kyoto rats and SHRs. The decreases in blood pressure and renal sympathetic nerve activity (RSNA) evoked by injecting kynurenic acid, a glutamate receptor blocker, into the RVLM were attenuated, and the increases in blood pressure and RSNA evoked by injecting bicuculline, a g-amino butyric acid (GABA) receptor blocker, into the RVLM were enhanced in AdMnSOD-transfected SHRs compared with adenovirus vectors encoding the bgalactosidase (AdLacZ) gene-transfected SHRs. Furthermore, the increases in blood pressure and RSNA evoked by injecting bicuculline into the PVN were attenuated in AdMnSOD-transfected SHRs compared with AdLacZ-transfected SHRs. Conclusion These findings suggest that ROS in the RVLM enhance glutamatergic excitatory inputs and attenuate GABAergic inhibitory inputs to the RVLM, thereby increasing sympathoexcitatory input to the RVLM from the PVN in SHRs.
Kidney-Induced Hypertension Depends on Superoxide Signaling in the Rostral Ventrolateral Medulla
Hypertension, 2010
Reactive oxygen species in peripheral cardiovascular tissues are implicated in the pathogenesis of 2 kidney-1 clip hypertension. We recently identified an imbalance between reactive oxygen species generation and oxidant scavenging in the rostral ventrolateral medulla (RVLM) of 2 kidney-1 clip in rats. We tested whether enhanced superoxide signaling in RVLM of 2 kidney-1 clip rats contributes to the chronic hypertension via sympathetic activation in conscious rats. We enhanced superoxide scavenging in RVLM by overexpressing cytoplasmically targeted superoxide dismutase using an adenoviral vector (Ad-CMV-CuZnSOD) in Wistar rats (male, 150 to 180 g) in which the left renal artery was occluded partially 3 weeks earlier. Hypertension was documented using radiotelemetry recording of arterial pressure in conscious rats for 6 weeks. Renovascular hypertension elevated both serine phosphorylation of p47phox subunit of NADPH and superoxide levels in RVLM. The elevated superoxide levels were normalized by expression of CuZnSOD in RVLM. Moreover, the hypertension produced in the 2 kidney-1 clip rats was reversed 1 week after viral-mediated expression of CuZnSOD. This antihypertensive effect was maintained and associated with a decrease in the low-frequency spectra of systolic blood pressure variability, suggesting reduced sympathetic vasomotor tone. The expression of CuZnSOD was localized to RVLM neurons, of which some contained tyrosine hydroxylase. None of the above variables changed in control rats receiving Ad-CMV-eGFP in RVLM. In Goldblatt hypertension, superoxide signaling in the RVLM plays a major role in the generation of sympathetic vasomotor tone and the chronic sustained hypertension in this animal model. (Hypertension. 2010;56:290-296.) Key Words: hypertension Ⅲ renal Ⅲ blood pressure Ⅲ heart rate Ⅲ brain Ⅲ free radicals
Redox biology, 2017
Angiotensin II (AngII) elicits the production of superoxide (O2(•-)) from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O2(•-) in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O2(•-) is causal in the development of AngII-induced hypertension, or if mitochondrial O2(•-) in the absence of elevated AngII is sufficient to increase blood pressure. Further, the tissue specific (i.e. central versus peripheral) redox regulation of AngII hypertension remains elusive. Herein, we hypothesized that increased mitochondrial O2(•-) in the absence of pro-hypertensive stimuli, such as AngII, elevates baseline systemic mean arterial pressure (MAP), and that AngII-mediated hypertension is exacerbated in animals with increased mitochondrial O2(•-) levels. To address this hypothesis, we generated novel inducible knock-down mouse models of manganese superoxide dismutase (MnSOD), the O2(•-) scaven...