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.

Systemic administration of pentoxifylline attenuates the development of hypertension in renovascular hypertensive rats.

There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 µg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.

Long-Term Outcomes of Endovascular Stenting for Blunt Renal Artery Injuries with Stenosis: A Report of Five Consecutive Cases.

BACKGROUND: Renal artery stenting is performed for renal artery injuries to preserve renal function and prevent renovascular hypertension. However, its indications are controversial and its long-term prognosis remains unknown. Here, we evaluate the characteristics and long-term outcomes of renal artery stenting for blunt renal artery injuries at our institution. METHODS: We retrospectively reviewed patients with blunt renal artery injuries who had been treated with stenting over a 12-year period at our institution. Five patients (three men and two women) were included. RESULTS: Trauma resulted from falls in three patients and motor vehicle accidents in two. All patients had experienced multiple injuries (median injury severity score, 24 [range, 16-48]; median revised trauma score, 5.9672 [4.0936-7.8408]; and median probability of survival, 0.689 [0.533-0.980]). All renal artery injuries involved stenosis because of traumatic arterial dissection or intimal tear; no cases of total occlusion were observed. No complications due to the intervention itself were observed. Although two patients developed reversible acute renal failure, none required long-term hemodialysis. One patient with renovascular hypertension was treated with antihypertensive agents for a month and subsequently became normotensive without further medication. All patients underwent postoperative computed tomography, which revealed no stent occlusion or renal atrophy. Renal scintigraphy for three patients demonstrated preserved differential renal function. All five patients survived. CONCLUSIONS: Renal artery stenting for hemodynamically stable blunt renal artery injuries with stenosis is suggested to be safe and helps in avoiding long-term hemodialysis and renovascular hypertension.

Effect of NF-κB inhibitor on Toll-like receptor 4 expression in left ventricular myocardium in two-kidney-one-clip hypertensive rats.

OBJECTIVE: To investigate the effects of an inhibitor of NF-κB, PDTC (pyrrolidine dithiocarbamate), on TLR4 (Toll-like receptor 4) expression in the left ventricle of Goldblatt hypertension rats. MATERIALS AND AND METHODS: Goldblatt rat model of two-kidney, one-clip (2K1C) hypertension was established in 70 healthy male rats. The rats were randomly divided into sham operation group (S group, n=20), non-drug intervention hypertension group (H group, n=25), and PDTC intervention group (P group, n=25). P group was injected with PDTC. The clip was inserted in the left renal artery of H group and P group (2K1C). Eight weeks after the operation, the rats were sacrificed and the samples of the left ventricle were collected. The concentration of AngII in the left ventricle was assessed by radioimmunoassay. RT-PCR was used to examine the mRNA expression of TLR4 in the left ventricle. Immunohistochemistry was adopted to examine the location of TLR4 and NF-κB in the myocardium. Victoria blue-Ponceau staining of Cardiac collagen was used to evaluate the degree of myocardial fibrosis. RESULTS: Eight weeks after the operation, caudal SBP, meridional end-systolic stress, left ventricular mass index, relative wall thickness, cardiac fibrosis degree, and the concentration of AngII in the left ventricle in P group were significantly lower than those in H group (p<0.01). In cardiac myocytes of S group and P group, TLR4 expression was diffused and presumably cytoplasmic. TLR4 mRNA expression in P group was significantly lower than that of H group (p<0.01). CONCLUSIONS: PDTC not only inhibited the activation of NF-κB, but decreased TLR4 expression and AngII content, indicating that the inflammatory signals and oxidative stress mediated by TLR4/NF-κB are involved in the occurrence and development of left ventricular remodeling. Intervention with TLR4/NF-κB and anti-inflammatory and anti-oxidative therapy may be a new target to reverse left ventricular remodeling.

Renal Artery Stenosis: To Stent or Not to Stent.

The column in this issue is supplied by Hassan N. Ibrahim, M.D., director of the Division of Kidney Diseases and Hypertension in the Department of Medicine at Houston Methodist Hospital and a fellow of the American Society of Nephrology. Dr. Ibrahim joined Houston Methodist in May 2017 after serving as a professor of medicine and chief of nephrology at the University of Minnesota.

Renovascular hypertension: Effects of mesenchymal stem cells in the contralateral hypertensive kidney in rats.

Mesenchymal stem cells (MSC) induced neovascularization and improved renal morphology of the stenotic kidney in 2 kidneys-1 clip (2K-1C) model of renovascular hypertension. The present study evaluated the effects of MSC in the contralateral hypertensive kidney. Three weeks after left renal artery occlusion, MSC were injected into the tail vein of the 2K-1C rats. Renal function and morphology were analyzed in both kidneys. Labeled MSC were found in stenotic and contralateral kidneys. Hypertensive 2K-1C animals presented increased circulating levels of Angiotensin II (Ang II) and renin. MSC prevented the progressive increase of blood pressure and reduced circulating Ang II and renin levels. Stenotic kidney showed reduced renal plasma flow (RPF) and glomerular filtration rate (GFR), whereas the contralateral kidney had a tendency (p > 0.5) of reduction in GFR in spite of unchanged RPF. MSC treatment caused an improvement in GFR with no effect of on RPF in the stenotic kidney. Contralateral kidney showed increased diuresis and natriuresis that were even higher in MSC-treated animals, indicating that cell treatment improved the capacity of the contralateral kidney to excrete sodium. Contralateral kidney expressed higher levels of inflammatory cytokines (IL-6, TNF-α) and signs of fibrosis, which were attenuated by MSC treatment. MSC treatment improved the stenotic kidney function, and it was also beneficial to the contralateral hypertensive kidney because it improved the morphology and preserved its capacity to excrete sodium.

To Stent or Not to Stent? Update on Revascularization for Atherosclerotic Renovascular Disease.

Renal artery stenosis (RAS) is increasingly encountered in clinical practice. The two most common etiologies are fibromuscular dysplasia (FMD) and atherosclerotic renal artery disease (ARAS), with the latter accounting for the vast majority of cases. Significant RAS activates the renin-angiotensin-aldosterone system and is associated with three major clinical syndromes: ischemic nephropathy, hypertension, and destabilizing cardiac syndromes. Over the past two decades, advancements in diagnostic and interventional techniques have led to improved detection and the widespread use of endovascular renal artery revascularization strategies in the management of ARAS. However, renal artery stenting for ARAS remains controversial. Although several studies have demonstrated some benefit with renal artery revascularization, this has not been to the extent anticipated or predicted. Moreover, these trials have significant flaws in their study design and are hampered with inherent bias which make their interpretation challenging. In this review, we evaluate the existing body of evidence and offer an approach to the management of patients with ARAS in light of the current literature. From the data provided, identification of subgroup of patients, namely, those with a hemodynamically significant RAS in the context of progressive renal insufficiency and/or deteriorating arterial hypertension, seems possible and may derive clinical benefit from ARAS stent revascularization. Appropriate patient selection is therefore the key and more robust studies are required.

Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^.

Ischemic nephropathy: more than a simple renal artery narrowing.

Renal artery stenosis in elderly patients is mainly caused by atherosclerosis. The prevalence of this disorder in patients with chronic kidney diseases is reported to be 0.5% to 5.5%. However, because the patients with atherosclerotic renal artery disease are mostly asymptomatic, the true prevalence is expected to be higher. Renovascular hypertension and ischemic nephropathy are two main consequences of this disease, but it is difficult to determine in which patient the progress of stenosis may cause these syndromes. The big challenge in renal artery stenosis is how to manage the patients. In the past 70 years, it has been believed that simply maintaining of kidney perfusion by opening the stenosis could control blood pressure and preserve kidney function. Nowadays, the blood pressure can be controlled well by medical treatment without the need for revascularization; however, management of ischemic nephropathy remains a dilemma. With advancements in understanding the pathophysiology of changes in the parenchyma of the kidney after stenosis, it is now generally accepted that only a minority of patients with ischemic nephropathy will benefit from revascularization. Nonetheless, finding these patients is critical and need more randomized trials to show who mostly benefit from revascularization and when it may save the kidney.

Granulocyte colony stimulating factor prevents kidney infarction and attenuates renovascular hypertension.

BACKGROUND: G-CSF is a critical regulator of hematopoietic cell proliferation, differentiation and survival. It has been reported that G-CSF attenuates renal injury during acute ischemia-reperfusion. In this study we evaluated the effects of G-CSF on the renal and cardiovascular systems of 2K1C hypertensive mice. METHODS: Male C57BL/6 mice were subjected to left renal artery clipping (2K1C) or sham operation and were then administered G-CSF (100 µg/kg/day) or vehicle for 14 days. RESULTS: Arterial pressure was higher in 2K1C + vehicle animals than in 2K1C + G-CSF (150±5 vs. 129±2 mmHg, p<0.01, n=8). Plasma angiotensin I, II and 1-7 concentrations were significantly increased in 2K1C + Vehicle when compared to the normotensive Sham group. G-CSF prevented the increase of these vasoactive peptides. The clipped kidney/contralateral kidney weight ratio showed a less atrophy of the ischemic kidney in the treated group (0.50±0.02 vs. 0.66±0.01, p<0.05). The infarction area in the clipped kidney was completely prevented in 7 out of 8 2K1C + G-CSF mice. Administration of G-CSF protected the clipped kidney from apoptosis. CONCLUSION: Our data indicate that G-CSF prevents kidney infarction and markedly attenuates the increases in plasma angiotensin levels and hypertension in 2K1C mice, reinforcing the protective effect of G-CSF on kidney ischemia.

The sympathetic nervous system and new nonpharmacologic approaches to treating hypertension: a focus on renal denervation.

The sympathetic nervous system is activated in a variety of cardiovascular and metabolic diseases. This is particularly the case for essential hypertension, in which various indices of adrenergic activity, such as plasma norepinephrine, norepinephrine spillover, and sympathetic nerve firing rate, are all well above the reference range of values, thereby documenting sympathetic overdrive. Evidence is available that sympathetic neural factors participate in disease progression, as well as in the development of cardiac and renal organ damage. These findings represent the rationale for therapeutic interventions that counteract the adrenergic overdrive in the hypertensive state. This paper, after reviewing the key findings of the neuroadrenergic abnormalities occurring in hypertension, examines the rationale and the technical details, as well as the results achieved so far, with the use of a new technique that allows the elimination of afferent and efferent innervation of the kidney in resistant hypertension, ie, the ablation of renal nerves. Strengths and potential limitations of the renal denervation approach are briefly addressed.

Atherosclerotic renal artery stenosis: update on management strategies.

PURPOSE OF REVIEW: Atherosclerotic renal artery stenosis (ARAS) usually occurs in patients at high risk of vascular disease, and is associated with increased mortality. The primary goals of ARAS treatment include the control of blood pressure (BP), the improved renal function, and the benefit on cardiovascular events. Although medical therapy remains the standard approach to the management of ARAS, percutaneous transluminal renal angioplasty (PTRA) revascularization can be a therapeutic option under certain conditions. RECENT FINDINGS: Recent evidence confirms that ARAS increases cardiovascular risk, independent of BP and renal function. This suggests that revascularization might potentially improve overall prognosis, but no data are available currently. In cases of significant ARAS, the accepted indications for PTRA are uncontrollable hypertension, gradual or acute renal function decline with the use of agents blocking the renin-angiotensin-aldosterone system, and recurrent flash pulmonary edema. The key point of treatment success remains in all cases a careful patient selection. SUMMARY: Although the atherosclerotic lesions of the renal arteries tend to progress over time, the anatomical lesion progression is not always associated with changes in BP. Furthermore, a poor correlation was noted between the degree of anatomic stenosis and glomerular filtration rate. The high cardiovascular risk warrants aggressive pharmacological treatment to prevent progression of the generalized vascular disorder. Ongoing trials will show whether PTRA revascularization has added, long-term effects on BP, renal function, and cardiovascular prognosis. With or without PTRA revascularization, medical therapy using antihypertensive agents, statins, and aspirin is necessary in almost all cases.

Managing diabetic nephropathy.

The earliest sign of DN is the development of microalbuminuria which is associated with a significant risk of both progressive renal failure and premature death from cardiovascular disease. Optimal glycaemic and BP control, including the use of RAAS blocking drugs, can prevent, slow and even reverse the processes causing DN.

Vitamin C prevents DNA damage induced by renovascular hypertension in multiple organs of Wistar rats.

The aim of this study was to investigate, through the single-cell gel (comet) assay, whether vitamin C is able to protect against renovascular hypertension-induced genotoxicity in multiple organs. A total of 32 male Wistar rats were divided into four groups: negative control (n = 6); animals treated with vitamin C (n = 6); hypertensive rats (n = 10) and hypertensive rats and treated with vitamin C (n = 10). Hypertension was induced as a result of partial obstruction of the left renal artery by means of a silver clip during 6 weeks. Vitamin C was administered at 150 mg/kg during 7 consecutive days before the end of the experimental period. The results showed that vitamin C was able to protect blood cells against hypertension-induced genotoxicity. Brain, liver and heart cells were also protected by vitamin C following hypertension-induced genotoxic damage. Regarding blood pressure, vitamin C reduced the hypertensive state. In conclusion, our results suggest that vitamin C can prevent hypertension-induced DNA damage in blood, liver, brain and heart cells as well as to normalize the blood pressure of rats.

Antioxidant treatment with tempol and apocynin prevents endothelial dysfunction and development of renovascular hypertension.

BACKGROUND: Two-kidney-one-clip (2K-1C) rats develop renovascular hypertension associated with endothelial dysfunction and elevated levels of oxidative stress. The role of oxidative damage is unknown in vascular dysfunction coupled with 2K-1C hypertension. The aims of this study were to evaluate the effects of chronic treatment with a superoxide dismutase (SOD) mimetic (tempol) and an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (apocynin) on the development of hypertension, endothelial dysfunction, and oxidative damage in 2K-1C rats. METHODS: 2K-1C rats and sham-operated rats were treated with tempol or apocynin for 40 days, while the corresponding nontreated groups received tap water. Blood pressure (BP), mesenteric arterial reactivity, plasma and mesentery oxidative damage, mesenteric protein expression, and antioxidant activities were compared among the four groups. RESULTS: Chronic treatment with tempol (1 mmol/l) or apocynin (33 microg/kg/day) impaired the development of hypertension in 2K-1C rats and did not change the BP in control animals. The reduction in vasodilatory effect induced by acetylcholine (ACh) in the mesenteric arterial beds (MABs) of 2K-1C rats was restored by tempol and apocynin. Plasma and mesentery levels of malondialdehyde (MDA) were higher in 2K-1C rats, and these levels were significantly reduced by the administration of tempol and apocynin. Mesenteric SOD activity and expression were higher in 2K-1C rats than in the controls, and treatment with tempol resulted in a reduction in SOD activity. CONCLUSIONS: The data suggest that a compromised mechanism of antioxidant defense and an increase in oxidative damage contribute to the development of hypertension and associated vascular dysfunction in 2K-1C rats, and that tempol and apocynin prevent these effects.

Influence of ATII blockers and calcium channel blockers on renal vascular resistance in patients with essential hypertension.

Doppler can evaluate renal vascular resistance, and resistance index (RI) highly correlates with blood pressure and renal function in various pathological conditions. Purpose of the study was to measure and compare renal Doppler indices in patients with newly-diagnosed essential hypertension (EH) and in healthy subjects; to determine changes of Doppler indices in patients after six-months monotherapy with either the AT II blocker (valsartane) or calcium channel blocker (niphedipine); to determine which drug has better renoprotective effect. 65 healthy controls were examined, as well as 69 patients with the newly-diagnosed EH, without signs of the target organ damage. Duplex Doppler US of interlobar intrarenal arteries was performed, and RI, acceleration index (AI) and acceleration time (AT) measured. Antihypertensive monotherapy was performed with vaslartane in 34 patients and with niphedipine in 35 patients. Doppler was repeated after the six-months therapy. RI in patients with the 1. stage of EH is significantly higher compared to the controls (p < 0.001), and significantly lower compared to the stage 2. of EH (p < 0.001). The significant decrease of systolic (p < 0.001) and dyastolic blood pressure (BP) (p < 0.001) was noted after the therapy. RI in healthy examinees (RI = 0.59 +/- 0.023) is significantly lower than in EH (RI = 0.66 +/- 0.26) (p < 0.001), while AI is significantly higher (p < 0.001), and AT is significantly lower (p < 0.001). In patients treated with valsartane and those treated with niphedipine, the RIs are significantly lower than before (p < 0.001), while AIs were significantly higher, and ATs were significantly lower after the therapy after the therapy with both drugs. RIs in patients treated with valsartane (RI = 0.615 +/- 0.036) are significantly lower than RIs of patients treated with niphedipine (RI = 0.642 +/- 0.030) (p < 0.01) after therapy. Regression analysis for the predictive values of RI, AT, AI in relation to the age-standardized values of systolic and diastolic BP of healthy examinees and patients with hypertension has demonstrated that RI is the strongest and statistically significant predictor in all groups of examinees. Six-months monotherapy of EH with valsartane or with niphedipine is equally efficient in the decrease of the blood pressure, but valsartane has more favourable effect on kidney. Resistance index measured in intrarenal arteries is the best parameter of Doppler spectrum in the evaluation of the effects of antihypertensive therapy on the kidney.