Obesity-related Hypertension Research Articles

Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: A multicenter, randomized, parallel-group controlled trial (ATH-D-14-01021.R2)

ObjectiveThere is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho-san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity. MethodsThe study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization. ResultsDaytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0 ± 3.3 vs −1.0 ± 3.3%; p = 0.006). ConclusionThe BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment. Clinical trial registrationUMIN000003878.

English

INTRODUCTION: Exercise is an important part of keeping adolescents healthy. The prevalence of obesity-related hypertension, in children and adolescents is on the rise. Exercise regimen can reverse or retard the rate of progression from prehypertension to hypertension in adolescents. The incidence of lung diseases including bronchial asthma is high in adolescent age group. There are gender differences in cardiopulmonary changes with exercise. The pulmonary function testing during exercise is often used for further assessment and determining the degree of airway impairment and response to treatment. The present study was performed to study the effect of various intensity of exercise on cardiopulmonary variables and to evaluate quantitative relationship between the variables. MATERIALS AND METHODS: The present study is carried out in a group of 100 healthy First year medical students of both sexes, who were not regular athletes. The subjects being medical students presented an added advantage of belonging to matching age groups of between 18-21 years of comparable physical standards and also medically screened at the time of admission. Before undertaking the exercise regimen blood hemoglobin concentration, RMV, MVV, FVC, FEV1, PEFR, RR, HR and Blood Pressure (BP) were determined in all the subjects. Then the subject exercised on a bicycle ergometer with incremental loads. The Pulse Rate of the subject is noted and mentioned as the heart rate per minute. During the exercise the pulse was monitored by a pulse Oximeter. Blood Pressure was manually measured using standard mercury sphygmomanometer. The recordings before exercise, during exercise and 30 minutes after end of exercise of FVC, FEV-1 and PEFR were measured using a digital spirometer. RESULTS: All the observations recorded in Group-A (Boys) subjects and of Group-B (Girls) subjects were noted. The arithmetical mean, standard deviation and standard error were calculated for each parameter. Paired't' Test was done and the degree of relationship between the variables was assessed by finding the coefficient of correlation. The results of study demonstrated that high intensity exercise produced significant changes in heart rate and systolic blood pressure. The rise in heart rate in Group-A subjects was 120% (P<0. 001) and in Group-B subjects was 116% (P<0. 001). Study demonstrated an increase of systolic blood pressure in Group-A subjects by 26. 64% (P<0. 001) during exercise and in Group-B subjects the increase was 27. 24% (P<0. 001). The diastolic blood pressure in our study showed a minimal decrease. In Group-A subjects the decrease of diastolic blood pressure was 2. 99% (P<0. 001) and in Group-B subjects the decrease was 2. 96% (P<0.001). Exercise induced bronchospasm in asthmatics cause airway obstruction leading to fall in PEFR values with exercise. However in normal subjects there is no airway obstruction seen in mild and moderate exercise SUMMARY AND CONCLUSION: cardiovascular variables of Heart Rate and Systolic and the diastolic pressure varied depending on the severity of exercise. Moderate exercise regimen may reduce diastolic pressure and the rate of progression from prehypertension to hypertension in adolescents. Measurement of pulmonary function subsequent to exercise could provide useful information about

Leptin i mehanizam delovanja leptina

Leptin is a hormone produced by the adipose tissue, which has effects on the central nervous system. Leptin is bound to its Ob receptor on hypo-thalamic neurons to inhibit feeding behavior and to increase sympathetically-mediated thermogenesis. In addition to anorexia and thermogenesis, leptin also has direct peripheral and central nervous system-mediated effects on the endocrine, vascular, hematopoietc, immune and musculoskeletal systems. Leptin accomplishes its effects using distributed network of leptin receptors and differential molecular signaling pathways. Leptinemia is increased in obesity because of increased adipocyte mass, but obese subjects exhibit resistance to the anorexic and metabolic effects of leptin. However, multiple studies have shown that leptin can increase sympathetic nerve activity to non-thermogenic tissues in rodents causing obesity-related hypertension. One potential explanation of this paradox is selective leptin resistance. Compared with large and persuasive number of studies on the sympathetic and blood pressure effects of leptin in experimental animals, relatively little attention was given to these effects of leptin in humans. This review article presents recent findings related to leptin and its mechanism of action, and also the role of leptin in patophysiological conditions.

Impact of obesity on kidney function and blood pressure in children.

In recent years, obesity has become an increasingly important epidemic health problem in children and adolescents. The prevalence of the overweight status in children grew from 5% to 11% from 1960s to 1990s. The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease (CKD) and hypertension. Results of several studies have demonstrated that obesity and metabolic syndrome were independent predictors of renal injury. The pathophysiology of obesity related hypertension is complex, including activation of sympathetic nervous system, renin angiotensin aldosterone system, hyperinsulinemia and inflammation. These same mechanisms likely contribute to the development of increased blood pressure in children. This review summarizes the recent epidemiologic data linking obesity with CKD and hypertension in children, as well as the potential mechanisms.

Is novel adipocytokine, omentin, a therapeutic target for obesity-related hypertension?

これまで脂肪組織は，単にエネルギーを蓄える貯蔵庫のようなものと考えられていた．しかし近年，脂肪組織は様々な生理活性物質（サイトカイン）を分泌することが認識されるようになり，これらはアディポサイトカインと呼ばれている．肥満により肥大化した脂肪組織において，アディポサイトカインの分泌は増減する．その結果，血中アディポサイトカインのバランス（善玉vs.悪玉）は不均衡となり，高血圧症や2型糖尿病，動脈硬化症などメタボリックシンドロームに関わる疾患の発症リスクが高まる．Omentinは2005年に大網脂肪組織中で同定された，313個のアミノ酸からなる比較的新規のアディポサイトカインである．Omentinは健常体では皮下脂肪よりも内臓脂肪組織に多く発現しており，近年の疫学調査により，その血中濃度は肥満症や高血圧症，2型糖尿病，アテローム性動脈硬化症，慢性腎不全，心臓病などの発症率と負の相関関係を示すことが明らかになった．よってomentinは，合併症を発症しない単なる肥満からメタボリックシンドロームへの移行の鍵を握る，重要なアディポサイトカインであると推察される．しかし，omentinの生理的あるいは病態生理的役割に関する基礎的な検討は全くなされてこなかった．本稿ではomentinと高血圧症の関連に焦点を当て，高血圧発症・進展の病態プロセス（in vitro）と血圧（in vivo）に及ぼす影響に関する当研究グループの成果を中心にomentinの病態生理的役割について概説する．Omentinはこれまでに検討した様々な病態プロセスに対して抑制的に働くことから，omentinは肥満による高血圧症治療のターゲットとなり得る非常に魅力的な分子である可能性が示唆される．

The Thiazide-Sensitive Co-Transporter Promotes the Development of Sodium Retention in Mice with Diet-Induced Obesity

Background/Aims: Intravascular volume expansion due to sodium retention is involved in the pathogenesis of obesity-related hypertension. Institution of high fat diet (HFD) feeding leads to an initial state of positive sodium balance due to enhanced tubular reabsorption of sodium, but which tubular sodium transporters are responsible for this remains undefined. Methods: C57/Bl6 mice were fed control or HFD for 3 weeks. Blood pressures were recorded by tail cuff method. Sodium transporter expression and phosphorylation were determined by Western blotting. In vivo activity of NCC was determined using natriuretic responses to hydrochlorothiazide. Expression of NCC mRNA was determined using qPCR. Results: At 3 weeks HFD mice had significant weight gains compared to control mice, but blood pressures were not yet elevated. There were no changes in expression or phosphorylation of the bumetanide-sensitive cotransporter, NKCC2, or in expression of subunits of the amiloride-sensitive ion channel, ENaC. However, there were significant increases in mRNA and protein expression of the thiazide-sensitive co-transporter, NCC, in kidneys from HFD mice. Consistent with this, HFD mice had increased in vivo activity of NCC. Conclusions: Increased expression of NCC promotes the sodium loading response to institution of HFD feeding before onset of hypertension.

ASSA14-03-13 Superoxide-lowering Therapy with Tempol Improves Balance of Renal RAS Components in Obese Zucker Rats

Objective Oxidative stress plays an important role in the pathogenesis of hypertension, particularly associated with obesity-related hypertension. Increased oxidative stress leads to an imbalance of the natriuretic and antinatriuretic factors of the renal renin angiotensin system (RAS). We hypothesise that superoxide-lowering therapy using tempol reverses this imbalance resulting to natriuresis and diuresis, thus lowering the blood pressure of obese Zucker rats. Methods Lean and obese Zucker rats received regular or antioxidant enzyme superoxide dismutase (SOD) mimetic tempol (1.0 mmol/l) in the drinking water for 4 weeks. Results Results showed that, compared with lean rats, obese rats exhibited higher blood pressures, higher levels of renal oxidative stress, accompanied by increased natriuretic responses to AT 1 R antagonist (candesartan) and AT 2 R agonist (CGP-42112A) and reduced natriuretic response to MasR agonist (ang-[1–7]). Moreover, obese rats had higher levels of ACE, AT 1 R and AT 2 R, lower levels of ACE2 and Mas receptors in the kidney. All of the above-mentioned abnormalities were reversed to some degree by tempol treatment. Conclusion Our study indicates that superoxide-lowering therapy with tempol reverses the imbalance of renal RAS components in obesity-related hypertension, which would be helpful to restore the renal function and lower blood pressure.

Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia.

Obesity is causally linked to a number of comorbidities, including cardiovascular disease, diabetes, renal dysfunction, and cancer. Obesity has also been linked to pulmonary disorders, including pulmonary arterial hypertension (PAH). It was long believed that obesity-related PAH was the result of hypoventilation and hypoxia due to the increased mechanical load of excess body fat. However, in recent years it has been proposed that the metabolic and inflammatory disturbances of obesity may also play a role in the development of PAH. To determine whether PAH develops in obese rats in the absence of hypoxia, we assessed pulmonary hemodynamics and pulmonary artery (PA) structure in the diet-resistant/diet-induced obesity (DR/DIO) and Zucker lean/fatty rat models. We found that high-fat feeding (DR/DIO) or overfeeding (Zucker) elicited PA remodeling, neomuscularization of distal arterioles, and elevated PA pressure, accompanied by right ventricular (RV) hypertrophy. PA thickening and distal neomuscularization were also observed in DIO rats on a low-fat diet. No evidence of hypoventilation or chronic hypoxia was detected in either model, nor was there a correlation between blood glucose or insulin levels and PAH. However, circulating inflammatory cytokine levels were increased with high-fat feeding or calorie overload, and hyperlipidemia and oxidant damage in the PA wall correlated with PAH in the DR/DIO model. We conclude that hyperlipidemia and peripheral inflammation correlate with the development of PAH in obese subjects. Obesity-related inflammation may predispose to PAH even in the absence of hypoxia.

Obesity-related hypertension: possible pathophysiological mechanisms.

Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine.

Optimum antihypertensive therapy: does adiposity matter?

Given that at least 75% of patients with hypertension are obese, it is no coincidence that the continuing obesity epidemic is driving the increasing incidence of hypertension. 1 Landsberg L Aronne LJ Beilin LJ et al. Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment. A position paper of the Obesity Society and the American Society of Hypertension. J Clin Hypertens. 2013; 15: 14-33 Crossref Scopus (266) Google Scholar Physicians have questioned whether the benefits of blood pressure lowering for cardiovascular disease might depend, in part, on choice of antihypertensive drugs (as shown in ACCOMPLISH 2 Jamerson K Weber MA Bakris G et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 359: 2417-2428 Crossref PubMed Scopus (1728) Google Scholar ) and that the choice of drugs should vary with the state of adiposity. 3 Weber MA Jamerson K Bakris GL et al. Effects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trial. Lancet. 2013; 381: 537-545 Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar Effects of blood pressure lowering on cardiovascular risk according to baseline body-mass index: a meta-analysis of randomised trialsWe found little evidence that selection of a particular class of blood pressure-lowering drug will lead to substantially different outcomes for individuals who are obese compared with those who are lean. Full-Text PDF

EHMTI-0077. Obesity-related intracranial hypertension in the rat – a possible idiopathic intracranial hypertension (IIH) model?

EHMTI-0077. Obesity-related intracranial hypertension in the rat – a possible idiopathic intracranial hypertension (IIH) model?

Adipokines: novel players in resistant hypertension.

Resistant hypertension (RH) is a multifactorial disease, frequently associated with obesity and characterized by blood pressure above goal (140/90 mm Hg) despite the concurrent use of ≥3 antihypertensive drugs of different classes. The mechanisms of obesity-related hypertension include, among others, aldosterone excess and inflammatory adipokines, which have demonstrated a significant role in the pathogenesis of metabolic syndrome and RH. This review aims to summarize recent studies on the role of the adipokines leptin, resistin, and adiponectin in the pathophysiology of RH and target-organ damage associated with this condition. The deregulation of adipokine levels has been associated with clinical characteristics frequently recognized in RH such as diabetes, hyperactivity of sympathetic and renin-angiotensin-aldosterone systems, and vascular and renal damage. Strategies to regulate adipokines may be promising for the management of RH and some clinical implications must be considered when managing controlled and uncontrolled patients with RH.

Abstract 333: Existence of Functional Norepinephrine Transport in Perivascular Adipose Tissue

Perivascular Tissue (PVAT) is a recent focus of studies for its regulation of blood vessel tone. Contraction to norepinephrine (NE) is reduced by PVAT through mechanisms not entirely clear. Loss of this anti-contractile function of PVAT occurs in obesity-related hypertension. We hypothesized that PVAT can remove NE from the blood vessel environment through transporters and reduce NE induced contraction in health. RT-PCR of mesenteric PVAT was positive for norepinephrine transporter (NET; Ct=33.2±1.4) and serotonin transporter (SERT; Ct=31.9±0.9) relative to beta-2-microglobulin. To study NE uptake in the healthy state, mesenteric and aortic PVAT from the male Sprague Dawley rat was incubated with 10 μM NE after pre-incubation with an inhibitor of transport (10 μM desipramine to inhibit NET and SERT, 100 μM corticosterone to inhibit organic cation transporter 3) or vehicle and quantified by HPLC for NE. Desipramine plus corticosterone inhibited NE uptake in mesenteric PVAT (figure) but desipramine (410.5±80.8 ng/g vs. 414.4±67.0 ng/g NE only; n=8) or corticosterone (225.0±26.1 ng/g vs. 319.2±35.9 ng/g NE only; n=5) alone did not, indicating a robust uptake capacity. In aortic PVAT, NE uptake was not inhibited by desipramine plus corticosterone (figure), desipramine (1763.5±460.8 ng/g vs. 1702.7±298.4 ng/g NE only; n=6), or corticosterone (1085.8±205.3 ng/g vs. 2245.8±506.8 ng/g NE only; n=4). Protein staining revealed bands positive for NET in mesenteric PVAT by Western blot. Taken together, we found that PVAT is a reservoir of NE that can remove NE from the blood vessel environment, an important finding to understand vasculature-PVAT interactions in health and disease.

Role of Renin-Angiotensin-Aldosterone System in Metabolic Syndrome and Obesity-related Hypertension

Several recent clinical trials show that blocking agents of the renin-angiotensin-aldosterone system (RAAS) reduce cardiovascular events in patients with metabolic syndrome based on insulin resistance and obesity, especially accumulated visceral fat. Our laboratory has focused on the relationship between the vascular RAAS and the action of insulin on the vasculature. We first revealed that the addition of insulin to cultured vascular smooth muscle cells (VSMC) markedly increases angiotensinogen and angiotensin II (Ang II) expression and production. Insulin addition also induces VSMC growth that is inhibited by the blockade of the RAAS by either ACEI or ARB which suggests a role for the RAAS in insulin-mediated growth. Insulin has a quite different effect on cultured vascular endothelial cells (EC) as it reduces angiotensinogen and renin expression. However, insulin added to EC induces a marked activation of ACE and the activated ACE promotes the conversion of Ang I to Ang II and cell growth under conditions of high insulin concentration. Ang II induces the progression of atherosclerosis through the production of oxidative stress that blocks insulin signaling and accelerates atherosclerosis. In this paper, we attempt to clarify the relationship between insulin resistance, the RAAS, and oxidative stress in vascular tissues to mimic in vivo conditions found in patients with metabolic syndrome and obesity-related hypertension as previously I reviewed in "Current Hypertension Reviews" in 2010 [1]. In addition, I update the relationships between vascular RAAS and insulin resistance for the last 4 years. JSH-2014 [2] states that the target goals of blood pressure (BP) for diabetes patients is lower than 130/80 mmHg, whereas updated JNC 8 [3] and ESH-ESC 2013 [4] recommends the target BP was changed to <140/90 mmHg for hypertensive patients with diabetes. Patients with diabetes and hypertension have reduced mortality as well as improved cardiovascular and cerebrovascular outcomes with treatment to a goal SBP <150 mm Hg, but no randomized controlled trials support a goal <140/90 mm Hg. Despite this, the panel opted for a conservative recommendation in patients with diabetes and hypertension, opting for a goal level of <140/90 mm Hg in adult patients with diabetes and hypertension rather than the evidence based goal of <150/90 mm Hg [3, 5]. JSH-2014 recommends that the first choice of antihypertensive medication should be RAAS blockers such as ACE inhibitor or ARB. For the last several years, several large cohort clinical studies using ACEI and ARB have shown more favorable effects, but aldosterone receptor inhibitor (mineral corticoid receptor inhibitors; MR inhibitors) and Renin Inhibitors have been withdrawn. Some studies showed the strong support to use these medications for diabetic patients. This review will discuss the relationships between vascular RAAS and insulin resistance in patients with hypertension and diabetes as previously reviewed with new updated findings for the last 4 years, and clinical implications based on updated JNC-8, ESH-ESC2013 and JSH-2014.

Central nervous system dysfunction in obesity-induced hypertension.

The activation of the sympathetic nervous system is a major mechanism underlying both human and experimental models of obesity-related hypertension. While insulin and the adipokine leptin have long been thought to contribute to obesity-related neurogenic mechanisms, the evidence is now very strong that they play a major role, shown particularly in animal studies using selective receptor antagonists. There is not just maintenance of leptin's sympatho-excitatory actions as previously suggested but considerable amplification particularly in renal sympathetic nervous activity. Importantly, these changes are not dependent on short-term elevation or reduction in plasma leptin or insulin, but require some weeks to develop indicating a slow "neural adaptivity" within hypothalamic signalling. These effects can be carried across generations even when offspring are raised on a normal diet. A better understanding of the underlying mechanism should be a high research priority given the prevalence of obesity not just in the current population but also for future generations.

Hypertension and Obesity: Correlates With Renin‐Angiotensin‐Aldosterone System and Uric Acid

Arterial hypertension, obesity, the renin-angiotensinaldosterone system (RAAS), and uric acid are all independently ligated to an increased cardiovascular (CV) risk. Arterial hypertension and obesity are among the 20 leading risk factors that increase the mortality of the general population with hypertension, which is number one. In turn, obesity is one of the most common factors responsible for the development of arterial hypertension. On the other hand, the RAAS and uric acid have been shown to participate independently in the development and maintenance of arterial hypertension, as well as in the mechanisms leading to the development of hypertension in obesity. Furthermore, RAAS as well as uric acid have been shown to be related to an increase in CV morbidity and mortality in hypertension and obesity. In fact, uric acid could play a role in the epidemic of obesity-related metabolic syndrome and cardiorenal disease. In this issue of The Journal of Clinical Hypertension, Zhang and colleagues expand the knowledge of the participation of the RAAS and uric acid in the pathogenesis of hypertension in obesity. The authors describe that serum uric acid is strongly related to angiotensinogen in an obesity-dependent manner in untreated hypertensive patients. They also describe that serum uric acid seems to contribute to the enhancement of plasma angiotensinogen and could be involved in the pathophysiology of obesity-related hypertension where an increase in activity of RAAS is one of the mechanisms underlying the development and maintenance of arterial hypertension. The pathophysiological scene of hypertension in obesity is a vicious circle in which specific mechanisms can contribute at the same time to trigger others, leading to the progressive deterioration of the cardiorenal system. This crosstalk between hypertension and obesity is represented in the Figure where it is shown how these mechanisms are interconnected. In this context, hyperuricemia is strongly related to arterial hypertension. At the same time, increased sympathetic activity and increased RAAS are also mechanisms underlying hypertension and obesity, where the results of Zhang and colleagues also point to angiotensinogen as an important player in the pathogenesis of obesity hypertension. The high level of circulating angiotensinogen observed in untreated hypertensive obese patients is also likely

181 Elucidating The Role Of β3-receptors In Perivascular Adipose Tissue

IntroductionPerivascular adipose tissue (PVAT) has been shown by various studies to have an anti-contractile effect on the arteries it surrounds. The mechanism by which PVAT exerts its anti-contractile effect is...

Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK.

Enhanced tubular reabsorption of salt is important in the pathogenesis of obesity-related hypertension, but the mechanisms remain poorly defined. To identify changes in the regulation of salt transporters in the kidney, C57BL/6 mice were fed a 40% fat diet [high-fat diet (HFD)] or a 12% fat diet (control diet) for 14 wk. Compared with control diet-fed mice, HFD-fed mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. When we examined Na(+) transporter expression, Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) was unchanged in whole kidney and reduced in the cortex, Na(+)-Cl(-) cotransporter (NCC) and α-epithelial Na(+) channel (ENaC) and γ-ENaC were unchanged, and β-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of STE-20/SPS1-related proline-alanine-rich protein kinase (SPAK)/oxidative stress responsive 1 kinase (OSR1) was increased in kidneys from HFD-fed mice, and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic experiments. HFD-fed mice had reduced activating phosphorylation of AMP-activated protein kinase (AMPK) in the renal cortex. In vitro, activation of AMPK led to a reduction in phospho-SPAK/phospho-OSR1 in AMPK(+/+) murine embryonic fibroblasts (MEFs), but no effect was seen in AMPK(-/-) MEFs, indicating an AMPK-mediated effect. Activation of the with no lysine kinase/SPAK/OSR1 pathway with low-NaCl solution invoked a greater elevation in phospho-SPAK/phospho-OSR1 in AMPK(-/-) MEFs than in AMPK(+/+) MEFs, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto-unrecognized mediator of enhanced Na(+) reabsorption in obesity and identifies a new role for AMPK in regulating the activity of SPAK/OSR1.

Reduction of plasma aldosterone and arterial stiffness in obese pre- and stage1 hypertensive subjects after aerobic exercise.

Obesity-related hypertension is associated with increased activity of the renin-angiotensin-aldosterone system (RAAS), increasing arterial stiffness. Aerobic exercise decreases pulse wave velocity (PWV), therefore a treatment option for hypertension and obesity. Assess RAAS activity and PWV before and after 4 weeks of aerobic training in unmedicated, pre-to-stage-1 hypertensives. Ten obese subjects (52±3.2 years, body mass index=33.5±1.4) performed 30 min of aerobic exercise on a treadmill 3 days per week at 65% of peak oxygen consumption (VO2peak). Descriptive characteristics, systolic and diastolic blood pressure (SBP and DBP), PWV, and a blood draw was performed at baseline, following the 4-week control and training interventions. No differences in descriptive characteristics during the control period were observed, however, a significant decrease in plasma aldosterone (ALDO) (255.4±75 to 215.8±66 pg ml(-1), P=0.001), SBP (140±12 to 136±10.4 mm Hg; P=0.02), DBP (89±4.2 to 85±6.3 mm Hg; P=0.03) and central PWV (11.2±0.6 to 9.8±0.8 m s(-1); P=0.04) was shown pre-to-post exercise training. Four weeks of moderate-intensity aerobic training in obese, hypertensives decreases plasma ALDO independently of body weight and is significantly correlated to decreases in PWV reductions.

The pathophysiology of hypertension in patients with obesity.

The combination of obesity and hypertension is associated with high morbidity and mortality because it leads to cardiovascular and kidney disease. Potential mechanisms linking obesity to hypertension include dietary factors, metabolic, endothelial and vascular dysfunction, neuroendocrine imbalances, sodium retention, glomerular hyperfiltration, proteinuria, and maladaptive immune and inflammatory responses. Visceral adipose tissue also becomes resistant to insulin and leptin and is the site of altered secretion of molecules and hormones such as adiponectin, leptin, resistin, TNF and IL-6, which exacerbate obesity-associated cardiovascular disease. Accumulating evidence also suggests that the gut microbiome is important for modulating these mechanisms. Uric acid and altered incretin or dipeptidyl peptidase 4 activity further contribute to the development of hypertension in obesity. The pathophysiology of obesity-related hypertension is especially relevant to premenopausal women with obesity and type 2 diabetes mellitus who are at high risk of developing arterial stiffness and endothelial dysfunction. In this Review we discuss the relationship between obesity and hypertension with special emphasis on potential mechanisms and therapeutic targeting that might be used in a clinical setting.