Yuzaburo Uetake

Epigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension

How high salt intake increases blood pressure is a key question in the study of hypertension. Salt intake induces increased renal sympathetic activity resulting in sodium retention. However, the mechanisms underlying the sympathetic control of renal sodium excretion remain unclear. In this study, we found that β2-adrenergic receptor (β2AR) stimulation led to decreased transcription of the gene encoding WNK4, a regulator of sodium reabsorption. β2AR stimulation resulted in cyclic AMP-dependent inhibition of histone deacetylase-8 (HDAC8) activity and increased histone acetylation, leading to binding of the glucocorticoid receptor to a negative glucocorticoid−responsive element in the promoter region. In rat models of salt-sensitive hypertension and sympathetic overactivity, salt loading suppressed renal WNK4 expression, activated the Na+-Cl− cotransporter and induced salt-dependent hypertension. These findings implicate the epigenetic modulation of WNK4 transcription in the development of salt-sensitive hypertension. The renal β2AR-WNK4 pathway may be a therapeutic target for salt-sensitive hypertension.

Protective Effect of Potassium Against the Hypertensive Cardiac Dysfunction: Association With Reactive Oxygen Species Reduction

Potassium supplementation has a potent protective effect against cardiovascular disease, but the precise mechanism of it against left ventricular abnormal relaxation, relatively early functional cardiac alteration in hypertensive subjects, has not been fully elucidated. In the present study, we investigated the effect of potassium against salt-induced cardiac dysfunction and the involved mechanism. Seven- to 8-week–old Dahl salt sensitive rats were fed normal diet (0.3% NaCl) or high-salt diet (8% NaCl) with or without high potassium (8% KCl) for 8 weeks. Left ventricular relaxation was evaluated by the deceleration time of early diastolic filling obtained from Doppler transmitral inflow, the slope of the pressure curve, and the time constant at the isovolumic relaxation phase. High-salt loading induced a significant elevation of blood pressure and impaired left ventricular relaxation, accompanied by augmentation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in the cardiac tissue, measured by the lucigenin chemiluminescence method. Blood pressure lowering by hydralazine could not ameliorate NADPH oxidase activity and resulted in no improvement of left ventricular relaxation. Interestingly, although the blood pressure remained high, potassium supplementation as well as treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide dismutase mimetic, not only reduced the elevated NADPH oxidase activity but also improved the left ventricular relaxation. In conclusion, a high-potassium diet has a potent protective effect on left ventricular active relaxation independent of blood pressure, partly through the inhibition of cardiac NADPH oxidase activity. Sufficient potassium supplementation might be an attractive strategy for cardiac protection, especially in the salt-sensitive hypertensive subjects.

Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions.

Background Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors. Method To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague–Dawley rats. Results Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and −dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na+–H+ exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na+–H+ exchanger isoform 1. Conclusion These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.

Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH.

High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice

BackgroundIt is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome.MethodsWe examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice.ResultsHigh-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice.ConclusionsWe demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.

Oxidative Stress in Multiple Organ Damage in Hypertension, Diabetes and CKD, Mechanisms and New Therapeutic Possibilities

Hypertension, diabetes, hypercholesterolemia and chronic kidney disease (CKD) lead to cardiovascular (CV) events and cardiovascular death consists of main cause in mortality of those diseases. Understanding of pathophysiology that links them and CV events has been vigorously studied and several factors are believed to play roles such as NO, reninangiotensin system, and oxidative stress. It has been shown that those factors affect endothelial function and consequently organ circulation as well as function and viability of cells and organs. Despite overwhelming evidences in the consequences of experimental models of ROS-induced organ damage, large-scale clinical trials of former antioxidant therapies, such as vitamin C, vitamin E or -carotene, could not demonstrate satisfactory benefit to patients and they seemed to be harmful in some cases (Hennekens et al., 1996; Omenn et al., 1996; Virtamo et al., 1998; Hercberg et al., 1999; Lee et al., 1999; Yusuf et al., 2000; de Gaetano, 2001; Heart, 2002; Vivekananthan et al., 2003; Hercberg et al., 2004; KrisEtherton et al., 2004; Lonn et al., 2005). Several studies concluded that β-carotene supplementation increased the relative risk of death in patients with some types of cancer and had no benefit on patients with cardiovascular disease. Another study said vitamin E increased hemorrhagic stroke. Even antioxidant cocktails increased in all-cause motality (Omenn et al., 1996; Rosen et al., 2001a). So far, supplementation with vitamins C and E, either alone or in combination with each other or with other antioxidant vitamins, does not appear to be efficacious for the treatment of cardiovascular disease (Lonn et al., 2005). We investigated role of oxidative stress in consequences of multiple organ damages in mouse and possible new therapeutic agent.

Reuse of cardiac organs in transplantation: an ethical analysis

BackgroundThis paper examines the ethical aspects of organ transplant surgery in which a donor heart is transplanted from a first recipient, following determination of death by neurologic criteria, to a second recipient. Retransplantation in this sense differs from that in which one recipient undergoes repeat heart transplantation of a newly donated organ, and is thus referred to here as “reuse cardiac organ transplantation.”MethodsMedical, legal, and ethical analysis, with a main focus on ethical analysis.ResultsFrom the medical perspective, it is critical to ensure the quality and safety of reused organs, but we lack sufficient empirical data pertaining to medical risk. From the legal perspective, a comparative examination of laws in the United States and Japan affirms no illegality, but legal scholars disagree on the appropriate analysis of the issues, including whether or not property rights apply to transplanted organs. Ethical arguments supporting the reuse of organs include the analogous nature of donation to gifts, the value of donations as inheritance property, and the public property theory as it pertains to organs. Meanwhile, ethical arguments such as those that address organ recycling and identity issues challenge organ reuse.ConclusionWe conclude that organ reuse is not only ethically permissible, but even ethically desirable. Furthermore, we suggest changes to be implemented in the informed consent process prior to organ transplantation. The organ transplant community worldwide should engage in wider and deeper discussions, in hopes that such efforts will lead to the timely preparation of guidelines to implement reuse cardiac organ transplantation as well as reuse transplantation of other organs such as kidney and liver.

Erratum: Corrigendum: Epigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension

Nat. Med. 17, 573–580 (2011); published online 17 April 2011; corrected after print 4 August 2011; corrected after print 5 April 2012 In the version of this article initially published, the image of the actin bands shown in Supplementary Figure 2b was mistakenly rotated 180 degrees. The image has been replaced with the bands in their correct orientation, and the densitometry shown for this blot has been recalculated, which does not affect the conclusions.

Adrenomedullin and Oxidative Stress in Vascular Damage and Metabolic Disease

We have studied the pleiotropic effects of adrenomedullin with knockout mice and found that it is a potent intrinsic antioxidant. Oxidative stress is related to cardiovascular as well as metabolic diseases. In this review, the coronary, pulmonary, and cerebrovascular damage that was observed in adrenomedullin-knockout mice is reviewed. An angiotensin II-loaded model, a hypoxia model, and a vascular occlusion model were applied to investigate vascular damage, and the results clarified the role of oxidative stress and the therapeutic potency of adrenomedullin in vascular protection. From in vivo and in vitro studies, adrenomedullin is known to antagonize oxidative stress by both inhibiting nicotinamide adenine dinucleotide phosphate oxidase and promoting the degradation of oxidative stress. In addition, the role of adrenomedullin in insulin resistance and obesity is discussed based upon the results of both clinical studies and basic research studies that used aged adrenomedullin-knockout mice. The pleiotropic effects of adrenomedullin suggest a number of new therapeutic targets in a variety of diseases.