The hydrogen sulfide donor 4-carboxyphenyl-isothiocyanate decreases blood pressure and promotes cardioprotective effect through reduction of oxidative stress and nuclear factor kappa B/matrix metalloproteinase (MMP)-2 axis in hypertension.

AIMS: Our aim was to evaluate whether the hydrogen sulfide (H2S) donor, 4-carboxyphenyl-isothiocyanate (4-CPI), exerts cardioprotective effect in the two kidney- one clip (2K-1C) rats through oxidative stress and MMP-2 activity attenuation and compare it with the classical H2S donor, Sodium Hydrosulfide (NaHS). MATERIALS AND METHODS: Renovascular hypertension (two kidneys-one clip; 2K-1C) was surgically induced in male Wistar rats. After two weeks, normotensive (2K) and hypertensive rats were intraperitoneally treated with vehicle (0.6 % dimethyl sulfoxide), NaHS (0.24 mg/Kg/day) or with 4-CPI (0.24 mg/Kg/day), for more 4 weeks. Systolic blood pressure (SBP) was evaluated weekly by tail-cuff plethysmography. Heart function was assessed by using the Millar catheter. Cardiac hypertrophy and fibrosis were evaluated by hematoxylin and eosin, and Picrosirius Red staining, respectively. The H2S was analyzed using WSP-1 fluorimetry and the cardiac oxidative stress was measured by lucigenin chemiluminescence and Amplex Red. MMP-2 activity was measured by in-gel gelatin or in situ zymography assays. Nox1, gp91phox, MMP-2 and the phospho-p65 subunit (Serine 279) nuclear factor kappa B (NF-κB) levels were evaluated by Western blotting. KEY FINDINGS: 4-CPI reduced blood pressure in hypertensive rats, decreased cardiac remodeling and promoted cardioprotection through the enhancement of cardiac H2S levels. An attenuation of oxidative stress, with inactivation of the p65-NF-κB/MMP-2 axis was similarly observed after NaHS or 4-CPI treatment in 2K-1C hypertension. SIGNIFICANCE: H2S is a mediator that promotes cardioprotective effects and decreases blood pressure, and 4-CPI seems to be a good candidate to reverse the maladaptive remodeling and cardiac dysfunction in renovascular hypertension.

Improving outcomes in atherosclerotic renovascular disease: importance of clinical presentation and multi-disciplinary review.

BACKGROUND AND OBJECTIVES: Atherosclerotic renal artery stenosis may cause hypertension, chronic kidney disease and heart failure, but large randomized control trials to date have shown no major additional benefit of renal revascularization over optimal medical management. However, these trials did not consider outcomes specifically in relation to clinical presentations. Given that atherosclerotic renal artery stenosis is a heterogenous condition, measures of success likely differ according to the clinical presentation. Our retrospective study objectives were to determine the effects of revascularization when applied to specific clinical presentations and after careful multi-disciplinary team review. METHODS: All patients presenting to our centre and its referring hospitals with radiological findings of at least one renal artery stenosis > 50% between January 2015 and January 2020 were reviewed at the renovascular multi-disciplinary team meeting with revascularization considered in accordance with international guidelines, notably for patients with anatomically significant renal artery stenosis, adequately sized kidney and presentations with any of; deteriorating kidney function, heart failure syndrome, or uncontrollable hypertension. Optimal medical management was recommended for all patients which included lipid lowering agents, anti-platelets and anti-hypertensives targeting blood pressure ≤ 130/80 mmHg. The effect of revascularization was assessed according to the clinical presentation; blood pressure and number of agents in those with renovascular hypertension, delta glomerular filtration rate in those with ischaemic nephropathy and heart failure re-admissions in those with heart failure syndromes. RESULTS: During this 5-year period, 127 patients with stenosis ≥ 50% were considered by the multidisciplinary team, with 57 undergoing revascularization (17 primarily for severe hypertension, 25 deteriorating kidney function, 6 heart failure syndrome and 9 for very severe anatomical stenosis). Seventy-nine percent of all revascularized patients had a positive outcome specific to their clinical presentation, with 82% of those with severe hypertension improving blood pressure control, 72% with progressive ischaemic nephropathy having attenuated GFR decline, and no further heart failure admissions in those with heart failure. Seventy-eight percent of patients revascularized for high grade stenosis alone had better blood pressure control with 55% also manifesting renal functional benefits. CONCLUSIONS: Multi-disciplinary team discussion successfully identified a group of patients more likely to benefit from revascularization based on 3 key factors: clinical presentation, severity of the renal artery lesion and the state of the kidney beyond the stenotic lesion. In this way, a large proportion of patients can clinically improve after revascularization if their outcomes are considered according to the nature of their clinical presentation.

Montelukast Ameliorates 2K1C-Hypertension Induced Endothelial Dysfunction and Associated Vascular Dementia.

BACKGROUND: Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT1) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis. OBJECTIVE: This research aims to examine the consequence of montelukast (specific CysLT1 antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals. METHODS: 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain's oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined. RESULTS: Montelukast in doses of 5.0 and 10.0 mg kg-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension- provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction. CONCLUSION: The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT1 receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.

Antihypertensive and Antioxidant Effects of an Aqueous Extract of Asafetida in Renovascular Hypertensive Rats.

Recently, the effect of an aqueous extract of asafetida on acute angiotensin II hypertensive rats was evaluated. The present study evaluated the antihypertensive and antioxidant effects of asafetida on a rat model of renovascular hypertension (RVH) using four groups. RVH was induced by clipping the renal artery; the sham group underwent surgery but without clipping. The RVH rats received losartan (Los, an AT1 receptor antagonist) or asafetida by gavage for 4 weeks. On the 28th day, the femoral artery was cannulated, and the systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were recorded. Finally, the levels of superoxide dismutase (SOD) activity, malondialdehyde (MDA), and total thiol content in the kidney and heart tissues were measured. In RVH rats, SBP and MAP significantly increased compared with the control. Los and the extract significantly reduced the changes in SBP, MAP, and HR that were induced in the RVH rats (P <0.05-0.001). In RVH rats, levels of MDA significantly increased and the content of total thiol and SOD decreased in both the heart and kidney tissues. Los plus the extract significantly decreased MDA and increased total thiol and SOD in the heart and kidney tissues. We concluded that an aqueous extract of asafetida gum has antihypertensive and antioxidant effects in the RVH rat model. The effect of the extract is similar to that of Los, which suggests that this effect of asafetida is mediated via an effect on the angiotensin Type I receptor.

The role of nitric oxide in renovascular hypertension: from the pathophysiology to the treatment.

Renovascular hypertension is one of the most relevant causes of secondary hypertension, mostly caused by atherosclerotic renovascular stenosis or fibromuscular dysplasia. The increase in angiotensin II production, oxidative stress, and formation of peroxynitrite promotes the decrease in nitric oxide (NO) availability and the development of hypertension, renal and endothelial dysfunction, and cardiac and vascular remodeling. The NO produced by nitric oxide synthases (NOS) acts as a vasodilator; however, endothelial NOS uncoupling (eNOS) also contributes to NO reduced availability in renovascular hypertension. NO donors and NO-derived metabolites have been investigated in experimental renovascular hypertension and have shown promissory effects in attenuating blood pressure and organ damage in this condition. Therefore, understanding the role of decreased NO in the pathophysiology of renovascular hypertension promotes the study and development of NO donors and molecules that can be converted into NO (such as nitrate and nitrite), contributing for the treatment of this condition in the future.

Outcomes Following the Endovascular Treatment of Renal Artery Stenosis Caused by Fibromuscular Dysplasia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Renal artery revascularization has been performed to improve blood pressure control and to cure hypertension in patients with renal artery fibromuscular dysplasia (RAFMD). We herein conducted a systematic review and meta-analysis of studies assessing outcomes associated with the treatment of hypertensive RAFMD patients via endovascular angioplasty in order to offer an up-to-date overview of the relative costs and benefits of this approach to revascularization in RAFMD patients. METHODS: We systematically searched the PubMed and Embase databases and the Cochrane Central Register for Controlled Trials to identify relevant studies published as of January 15, 2020. Key outcomes of interest in these studies included technical success, the incidence of perioperative complications, cure rates, and overall improvement rates. RESULTS: In total, we identified 36 relevant studies of 1916 total repairs conducted in 1191 patients. Of these included studies, 33 were retrospective, while 3 were prospective. The overall technical success rate across these studies was 94.3%. Rates of total, major, and minor complications in these pooled studies were 12.9%, 4.6%, and 7.4%, respectively. Pooled rates of cured hypertension and improved hypertension following angioplasty, defined according to study-specific criteria, were 37.0% [95% CI: 27.0%-47.0%] and 80.0% [95% CI: 75.0% to 84.0%], respectively, although these rates varied highly among studies. Cure rates for studies used current clinical definitions for substantial variations across studies. Cure rates in studies using current definitions of cured hypertension (blood pressure <140/90 mm Hg without treatment) were just 18.1% following angioplasty. Cure rates fell markedly with increasing mean patient age (OR associated with an increase in mean age of 10 years: -0.24 [95% CI: -0.44 to -0.04, P = 0.019] and with mean known duration of hypertension (OR associated with an increase in mean hypertension duration of 5 years: -0.09 [95% CI: -0.12 to -0.05, P = 0.001]). CONCLUSIONS: These findings suggest that endovascular treatment yielded moderate benefits to RAFMD patients, with substantial variation across studies. The blood pressure outcome was strongly influenced by patient age.

Insights from intravascular pressure measurement of renal artery revascularization in patients with fibromuscular dysplasia: The DYSART study.

OBJECTIVE: The indication of percutaneous renal transluminal angioplasty (PTRA) in fibromuscular dysplasia (FMD) is mainly based on renal artery stenosis (RAS) due to atherosclerosis criteria, which are not specific to FMD. Consequently, the selection of patients who could benefit from this treatment and its effectiveness remain uncertain. The aims of this study were to: (1) report the effects of PTRA guided by trans-stenotic pressure measurements on hypertension 7 months after treatment; (2) assess the impact of pressure measurement to guide treatment efficacy in comparison to visual angiographic parameters; and (3) evaluate the reproducibility and accuracy of the stenosis measurement using a 4F catheter in comparison to a pressure guidewire. METHODS: This prospective multi-centric study analyzed 24 patients with hypertension with RAS due to FMD that required PTRA. Clinical, duplex ultrasound, and angiographic indices were collected, and patients were followed up for 7 months (±1 month). Angiographic indices were measured twice both by a pressure guidewire and a 4F catheter. Assessment of procedural and clinical success of angioplasty was performed for all patients. RESULTS: Twenty-three patients (96%) had procedural success (considered as a post-PTRA translesional systolic gradient ≤10 mmHg or reduced by at least 80%) with a significant decrease in the systolic gradient after angioplasty (26.50 mmHg; [interquartile range, 16.75-38.75] vs 0.00 [interquartile range, 0.00-2.00]; P < .01). Three patients (12%) had complications, including two renal artery dissections and one partial renal infarction. Twenty-one patients (88%) were clinical responders to angioplasty at follow-up. Visual stenosis assessment showed a poor correlation with systolic gradient measurement before and after PTRA (R from -0.05 to 0.41; P = 0.06-0.82). High correlations were found between pressure measurements made by a 4F catheter and guidewire (R from 0.64 to 0.89; P ≤ .003). CONCLUSIONS: In patients selected by clinical indicators and duplex ultrasound, reaching a translesional systolic gradient ≤10 mmHg or reduced by at least 80% after angioplasty, promotes a high success rate for PTRA in hypertension due to FMD RAS.

Retrograde Recanalization for Proximal Occlusion of the Right Renal Artery through a Compensated Collateral Artery in a 10-year-old Patient.

BACKGROUND: To describe a retrograde recanalization for the proximal occluded lesion in right renal artery (RRA) in young patient with fibromuscular dysplasia (FMD). METHODS: A 10-year-old girl presented to our hospital with proximal RRA occlusion and refractory hypertension though she took anti-hypertension medicines. Her renin and aldosterone were beyond the normal level in both base state and excited state. Her glomerular filtration rate at right kidney was only 18.4 ml/min. Angiography revealed proximal RRA occlusion and a compensated collateral artery (CCA) from the infrarenal aorta to the RRA. She was thus diagnosed with focal FMD. A retrograde recanalization was performed through this CCA. RESULTS: Angioplasty and stenting were successfully performed to treat the proximal RRA occlusion. Postoperatively, the glomerular filtration rate in the right kidney improved. One-year follow-up revealed that, the blood pressure maintained at normal range without any antihypertensive agents. No other discomfort was complained. CONCLUSIONS: It is feasible to establish a working pathway with patient's compensated collateral artery to treat the renal artery occlusion.

Refractory hypertension secondary to renal artery stenosis with a honeycomb-like structure.

BACKGROUND: A honeycomb-like structure (HLS) is a rare abnormality characterized by a braid-like appearance. Angiograph and intravascular examination, including coherence tomography and intravascular ultrasound (IVUS), can further confirm the multiple intraluminal channels or honeycomb structure, which can also be described as looking like 'swiss cheese', a 'spider web' or a 'lotus root'. Previous studies have mostly reported this abnormality in coronary arteries, with a few cases in renal arteries. More information about the characteristics and development of HLS is needed. CASE PRESENTATION: A 69-year-old Han man with resistant hypertension received abdominal enhanced computerised tomography and was revealed to have left renal artery stenosis with the possibility of left renal infarction. Renal artery angiography confirmed a 95% stenosis located in the proximal segment of the left renal artery, and the middle segment was blurred with multi-channel-like blood flow. Further IVUS was performed and identified multiple channels surrounded by fibrous tissue. It was a rare case of HLS in the renal artery secondary to the thrombus, with organisation and recanalisation. Balloon dilatation and stent implantation at the proximal segment of the left renal artery were performed successfully. Blood pressure was well controlled after the procedure. CONCLUSIONS: The IVUS findings are helpful for forming interventional therapeutic strategies for HLS lesions in the renal artery.

Renal Artery Reconstruction for Refractory Hypertension Caused by Congenital Renal Artery Deficiency.

Renovascular hypertension is a common cause of secondary hypertension. According to the epidemiological survey, the prevalence of renovascular hypertension accounts for 1-5% of the population with hypertension. Most of the cases are associated with atherosclerosis and Fibromuscular Dysplasia (FMD). Owing to the lack of standard treatment, they will eventually develop into chronic kidney disease, which significantly affects the patient's quality of life. Hypertension is considered a prerequisite for renal artery surgery; renal function research is used to guide the treatment of unilateral lesions because endovascular intervention can only slightly improve hypertension and renal function. We advocate open surgery for patients with congenital dysplasia of renal vascular hypertension, in which the most common surgical operations are aortorenal artery bypass, renal artery endarterectomy, and renal artery replantation. This paper reports a rare case of renovascular hypertension. The patient was a 13-year-old female, and the operation was risky and complicated. He was diagnosed with a congenital absence of the right renal artery. The right renal function was recovered, and the blood pressure was well controlled after the Aorta-Right Renal Artery Bypass.

Responsiveness of afferent renal nerve units in renovascular hypertension in rats.

Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1-4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension.

Allisartan ameliorates vascular remodeling through regulation of voltage-gated potassium channels in hypertensive rats.

BACKGROUND: The objective of the present study was to determine the effect of allisartan, a new angiotensin II type 1 receptor antagonist on vascular remodeling through voltage gated potassium channels (Kv7) in hypertensive rats. METHODS: The study included a total of 47 Sprague Dawley (SD) rats. The animals were randomized to sham operation (n = 14), untreated hypertensive control group (n = 18) and allisartan treatment group (n = 15). Using renal artery stenosis, hypertension was induced in animals. Single dose of allisartan was administered intra-gastrically to animals in the allisartan treatment group and match placebo in the other 2 groups. Wire myography was used to measure the muscle tension in isolated mesenteric arteries from the animals. Real-time polymerase chain reaction was used to quantify the expression of Kv7 channel mRNA subunits. RESULTS: After 4 weeks of treatment, a significant decrease in mean arterial, systolic and diastolic blood pressure (SBP and DBP) was observed in allisartan treatment group compared to hypertension control group. The median arterial wall thickness and area/diameter ratio reduced significantly in treatment group compared to untreated hypertension group (P < 0.05). Wire myography demonstrated increased relaxation of mesenteric artery with increase in concentration of ML213. A significant up-regulation in the expression of all Kv7 mRNA subunits was observed in allisartan group compared to untreated hypertension group. CONCLUSIONS: From the results, allisartan was found to lower BP and preserve vascular remodeling through Kv7 channels.

Effects of Captopril and Losartan on Cardiac Stereology in Rats with Renovascular Hypertension.

Background: Captopril, an angiotensin-converting enzyme inhibitor, and losartan, an angiotensin II receptor blocker, are used for the treatment of hypertension, but their effects on cardiac stereology are unknown. This study, therefore, aimed to examine their effects on cardiac stereology in rats with renovascular hypertension. Methods: This study was conducted at Histomorphometry and Stereology Research Centre, and Cardiovascular Pharmacology Research Lab, Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, in August 2015 to August 2016. Fourty-eight rats were allocated to six groups (n=8 per each group): a sham group, which received a vehicle (distilled water) and five renal artery-clipped groups, which received the vehicle, captopril (50 or 100 mg/ kg/day), or losartan (25 or 50 mg/kg/day). After four weeks, the animals' systolic blood pressures (mm Hg) were measured, and the total volumes of their heart, myocardium, endocardium, matrix, and myocardial vessels (mm3), as well as the number of their cardiomyocytes, and Purkinje fibers were determined. Data were analyzed using one-way analysis of variance (ANOVA) followed by least significant difference (LSD) test. P value of equal to or less than 0.05 was considered significant. Results: The renal artery-clipped rats receiving the vehicle had a significantly higher systolic blood pressure (P<0.001); heart weight (g) (P<0.001); and total volume of the heart (P<0.001), myocardium (P=0.020), endocardium (P=0.009), and myocardial vessels (P=0.008); as well as a significantly lower number of cardiomyocytes (P=0.010) and Purkinje cells (P=0.005), than did the rats in the sham group. The renal artery-clipped rats receiving captopril or losartan had a significantly lower systolic blood pressure (P<0.001), heart weight (P=0.007), and total volume of the heart (P<0.001), myocardium (P<0.001), endocardium (P=0.027), and myocardial vessels (P=0.004) than did the renal artery-clipped rats receiving the vehicle. Neither captopril nor losartan prevented a reduction in the number of Purkinje cells, but captopril at the higher dose attenuated cardiomyocyte loss (P=0.010). Conclusion: Captopril and losartan lowered the systolic blood pressure and cardiac hypertrophy but failed to prevent Purkinje cell loss. Captopril only at the higher dose prevented cardiomyocyte loss. Captopril exerted a greater inhibitory effect on cardiac stereology, which warrants further research.

Intracranial Pressure During the Development of Renovascular Hypertension.

[Figure: see text].

Intracranial baroreflex is attenuated in an ovine model of renovascular hypertension.

We have previously shown that elevations in intracranial pressure (ICP) within physiological ranges in normotensive animals increase arterial pressure; termed the intracranial baroreflex. Hypertension is associated with alterations in reflexes which maintain arterial pressure however, whether the intracranial baroreflex is altered is not known. Hence, in the present study, we tested the hypothesis that in hypertension, physiological increases in ICP would not be accompanied with an increase in arterial pressure. Renovascular hypertension was associated with no change in heart rate, renal blood flow or ICP levels compared to the normotensive group. ICV infusion of saline produced a ramped increase in ICP of 20 ± 1 mmHg. This was accompanied by an increase in arterial pressure (16 ± 2 mmHg) and a significant decrease in renal vascular conductance. ICV infusion of saline in the hypertensive group also increased ICP (19 ± 2 mmHg). However, the increase in arterial pressure was significantly attenuated in the hypertensive group (5 ± 2 mmHg). Ganglionic blockade abolished the increase in arterial pressure in both groups to increased ICP. Our data indicates that physiological increases in ICP lead to increases in arterial pressure in normotensive animals but this is severely attenuated in renovascular hypertension.

Açaí Reverses Adverse Cardiovascular Remodeling in Renovascular Hypertension: A Comparative Effect With Enalapril.

ABSTRACT: This study aimed to determine if açai seed extract (ASE) could reverse pre-existing cardiovascular and renal injury in an experimental model of renovascular hypertension (2 kidney, 1 clip, 2K1C). Young male rats (Wistar) were used to obtain 2K1C and sham groups. Animals received the vehicle, ASE (200 mg/kg/d), or enalapril (30 mg/kg/d) in drinking water from the third to sixth week after surgery. We evaluated systolic blood pressure by tail plethysmography, vascular reactivity in the rat isolated mesenteric arterial bed (MAB), serum and urinary parameters, plasma inflammatory cytokines by ELISA, MAB expression of endothelial nitric oxide synthase and its active form peNOS by Western blot, plasma and MAB oxidative damage and antioxidant activity by spectrophotometry, and vascular and cardiac structural changes by histological analysis. ASE and enalapril reduced the systolic blood pressure, restored the endothelial and renal functions, and decreased the inflammatory cytokines and the oxidative stress in 2K1C rats. Furthermore, both treatments reduced vascular and cardiac remodeling. ASE substantially reduced cardiovascular remodeling and recovered endothelial dysfunction in 2K1C rats probably through its antihypertensive, antioxidant, and anti-inflammatory actions, supplying a natural resource for the treatment of renovascular hypertension.

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

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.