Current Hypertension Reviews - Volume 12, Issue 2, 2016

SIRT1 is an NAD-dependent deacetylase. One important role of SIRT1 is its deacetylation activity in the modulation of cell stress signals via epigenetics. In podocytes, SIRT1 regulates the expression of important genes such as PGC-1α, Foxo4, p65 and STAT3, which act to maintain podocyte function by modulating the levels of histone acetylation. Here, we confirmed that SIRT1 protects podocytes by maintaining PGC-1α via its deacetylase-activated transcriptional activity in mitochondria and podocytes. We then showed that the alteration of Foxo4 (forkhead box O4) acetylation and decrease in SIRT1 promote podocyte apoptosis in diabetic nephropathy, resulting in the gradual development of diabetic nephropathy. Next, we showed that advanced glycation end products (AGEs) induced p65 and STAT3 acetylation in human podocytes. Decreased Sirt1 activity in podocytes results in the development of proteinuria and kidney injury via the acetylation of p65 and STAT3. These findings suggest that the beneficial effects of SIRT1 in diabetic nephropathy act via the deacetylation of transcription factors. In addition to its essential role in regulating the epigenetics of podocytes, we recently showed that SIRT1 is necessary to maintaining the function of slit membranes and podocytes. The actin cytoskeleton becomes vulnerable to various stresses, including oxidative stress, which in turn leads to the derangement and effacement of foot processes, slit membrane dysfunction, and proteinuria. SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and changing cortactin localization, thereby maintaining the integrity of the actin cytoskeleton. We expect that SIRT1 will be shown to sufficiently suppress the development of kidney dysfunction and will be proven useful in the near future. The clinical application of SIRT1-activated chemical agents has just started, and results are eagerly anticipated.

We have recently published that tubular epithelial cells affect the podocyte epigenome though nicotinic acid metabolism in diabetic nephropathy (DN), and we have named this relationship “proximal tubule–podocyte communication”. In this review, we describe this novel mechanism in the early stage of DN, focusing on the function of renal tubular Sirt1 and Sirt1-related nicotinic acid metabolism. Mainly, we discuss the following three findings. First, we described the details of proximal tubule–podocyte communication. Second, we explained how Sirt1 regulates albuminuria via epigenetic mechanisms. This means that repeated high glucose stress triggers the initial changes in proximal tubules, which lead to the epigenetically irreversible glomerular damages. However, proximal tubular Sirt1 overexpression can rescue these changes. Our previous data indicated that the decrease in Sirt1 expression in proximal tubules caused the reduction in glomerular Sirt1 and the subsequent increase in glomerular Claudin-1. It seemed plausible that some humoral mediator is released from proximal tubules, migrates to podocytes and glomeruli, and affects Sirt1 expression in podocytes. Third, we mentioned a mediator connecting this communication, nicotinamide mononucleotide (NMN). We suggest the potential of Sirt1 or NMN as not only a therapeutic target but also as a prognostic marker of very early stage DN.

Recently it has been shown that epigenetic mechanisms are involved in initiation and progression of caridiovascular and metabolic diseases, including diabetes, obesity, atherosclerosis, heart failure, hypertension and kidney diseases. In these chronic diseases, various exogenous and endogenous stresses cause DNA damage, followed by DNA repair process. Accumulation of DNA damages and impaired repair process can lead to epigenetic changes, which may contribute to onset and progression of diseases. Recently we have shown that therapeutic effect of transcription factor KLF4 (Kruppel-like factor 4) in kidney glomerular epithelial cells (podocytes) on proteinuric kidney diseases through epigenetic mechanisms. Our result suggests the possibility of transcription factors as a target of selective epigenetic therapy. Moreover, we have reported that renin-angiotensin system (RAS) blockers, which are widely prescribed for the treatment of cardiovascular diseases, can restore epigenetic changes through KLF4 in part. These results suggest that activation of RAS causes epigenetic changes in disease states, and elucidation of the precise mechanism may lead to establishment of novel therapeutic target of kidney diseases. In this review we focus on DNA damage repair system and epigenetic modulators in disease states, and speculate a candidate for epigenetic therapy of kidney diseases.

Over the past several years, cancer treatments have expanded from usual chemotherapy standards with introduction of newer targeted therapies. As with chemotherapy, the targeted therapies also have unique side effects affecting various organ systems producing toxicities, such as cardiac and renal. This manuscript focuses on hypertension induced by vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKI). Hypertension due to these cancer therapies is important because these agents are now frequently used in common cancers. In addition, patients with cancer may not be treated in a comprehensive cancer center with experts available to manage the cancer and other side effects either from the malignancy or treatment of the malignancy. Especially in rural areas, patients are often managed or co-managed by a primary care provider with input from an oncologist that may not be nearby. Our aim is to provide an overview of the latest Federal Drug Administration (FDA) approved VEGF inhibitors and TKI’s causing hypertension so that others managing patients on these treatments may easily recognize hypertension attributable to these agents and feel comfortable and confident in providing appropriate management and treatment of this side effect. This update includes characteristics, such as mechanism of action, metabolism and route of administration, and management and treatment of hypertension with aspects such as the timing, duration and monitoring of these agents. In addition, an algorithm for monitoring and treating hypertension before, during and after treatment with these therapies is included. It is imperative for patients to have hypertension promptly treated to prevent complications so they may continue with these agents with the least interruption or discontinuation of treatment, ensuring the best benefit available in their cancer trajectory.

Raised blood pressure is common in ischaemic stroke and intracerebral haemorrhage and is an independent risk factor for unfavourable outcome. Yet, the approach to blood pressure management represents an unresolved issue in acute stroke treatment. The aim of this review is to present the current knowledge regarding the management of raised blood pressure in patients with acute ischaemic stroke or intracerebral haemorrhage. In ischaemic stroke, several large clinical trials have tested the efficacy of several strategies that lower blood pressure. Overall, blood pressure lowering in the acute phase has no beneficial effect and should not be included in routine clinical practice apart from when treating patients with very raised blood pressure or those who are eligible for thrombolytic treatment. These findings in patients with acute ischaemic stroke are in contrast with those in intracerebral haemorrhage. A recent clinical trial has strongly suggested a clinical benefit of blood pressure lowering during the first few hours in intracerebral haemorrhage, which have led to changes in international guidelines. An important unanswered question in blood pressure management in the acute phase of ischaemic stroke involves the first few hours, when there is still penumbral tissue at risk. Forthcoming trials may help to answer this remaining issue.

The most recent Cochrane reviews on oral antihypertensive drugs in pregnancy conclude that no substantial benefits for the mother or fetus are demonstrated so far. Whether this applies for a high-risk and diabetic pregnancy is doubtful. The aim of this short review is an introduction to the field of ambulatory blood pressure measurements in pregnancy and in particular in women with type 1 diabetes. Diabetic pregnancy is complicated with a 50% risk of hypertension/preeclampsia. In the nonpregnant, diabetic women minute increases in blood pressure as well as in albuminuria are forerunners for incipient and overt nephropathy. Medication is essential and can conserve renal function, modifying the risk of renal insufficiency. During pregnancy, renal insufficiency in women with diabetes leads to termination of pregnancy. Therefore, detection of minute changes based on reliable measurements in this high-risk population is invaluable to protect the mother’s kidney function and, if possible, prolong pregnancy for the benefit of the fetus. Estimates of risk by blood pressure evaluation in these women are influenced by pregnancy per se and diabetes vasculopathy. Several factors have to be considered as few monitors are validated for use in pregnancy and not many of the different methodologies have undergone thorough investigation. The use of absolute values of blood pressure have the advantage that fewer assumptions are necessary on how blood pressure behaves due to modes of evaluation and biological rhythm. Monitors should be chosen with care considering the clinical setting, timing, and population, which influences the outcome, thus, the monitors ought to be validated for the specific condition they are applied for. The strategy for the studies used for safe conclusions in this brief review was chosen with priority of the papers with the best, validated methodology on BP measurements, which is by no way guaranteed in numerous recent publications. Inherent characteristics of the measurements to be considered are reproducibility, consistency, precision, and trend over scale of measurement. Studies on these issues suggest that consistency and precision depend on which monitor is used. During pregnancy, the reproducibility and specificity depend on the timing and whether measurements are performed repeatedly. Over- and underestimations of blood pressure are typical for 24-h monitoring in high- as well as low risk pregnancies. Preeclampsia is associated with urinary albumin excretion rate, reduced night/day ratio, and elevated diurnal blood pressure from first trimester and onwards. However, due to blunting of the diurnal variation, the night/day rhythm provides no good prediction of preeclampsia. Diurnal measurement is a valuable estimate of blood pressure in terms of sensitivity, specificity, and predictive values.

Introduction: Prehypertension is considered a precursor of systemic arterial hypertension and a predictor of morbidity-mortality due to cardiovascular diseases, which are the main causes of death in Brazil and the world. Thus, early diagnosis and the adoption of therapeutic measures in cases of prehypertension can reduce cardiovascular risk. The aim of the present study was to perform a selective review of the literature to identify and discuss early endothelial changes in individuals with pre-hypertension. Results and Discussion: The findings indicate an increase in ET-1-mediated vasoconstrictor tone in prehypertension, with endothelial-dependent vasodilatation impairment. Moreover, significantly high levels of angiotensin, arginine and vasopressin were found in this group of patients. A reduction in endothelial fibrinolytic capacity was another important change found in patients with prehypertention and was associated with an increased risk for atherothrombotic events. Conclusion: The present findings demonstrate endothelial changes in individuals with prehypertension that contribute to the development of arterial hypertension as well as a high risk for cardiovascular events, underscoring the importance of the early adoption of optimized therapeutic measures for this population.

The pathophysiological mechanism of resistant hypertension (RH) is related to increased vascular smooth muscle tone and blood volume, exacerbation of the activity of the sympathetic system and hyperactivity of the renin-angiotensin-aldosterone system (RAAS), all of which are important regulatory mechanisms of blood pressure. Hypertension is associated with reduced endothelial homeostasis, and thus the best treatment would not only reduce blood pressure but also reverse endothelial injury. RH is associated with more serious vascular dysfunction, assessed by endothelium-dependent vasodilation and the presence of serum biomarkers. Arterial stiffness also constitutes an important independent factor that can determine risk of cardiovascular events in patients with RH; it is an important indicator of vascular changes, and is associated with cardiovascular mortality. Arterial stiffness can be assessed by 3 measures: central blood pressure, augmentation index (AIx) and pulse wave velocity (PWV). PWV is a recognized as main marker of the severity of vascular injury. The increase in central blood pressure caused by backward (reflected) waves can be evaluated as an index derived from an analysis of the central aortic blood pressure curve known as the AIx, and depends on the magnitude and time of the reflected waves and indirectly on heart frequency and arterial stiffness. The evaluation of patients with RH is focused on the identification of causes of hypertension guided by the clinical features of hypertension and metabolic, vascular, endocrine and family history.

Stroke is the second most common cause of death and the most common cause of disability worldwide. Up to 30% of ischaemic strokes are caused by carotid atherosclerosis, usually due to thromboemboli from an atherosclerotic plaque at the carotid bifurcation. High blood pressure is an important risk factor for atherosclerosis, the development of unstable carotid plaques, and ischaemic strokes. Differentiation between asymptomatic and symptomatic carotid atherosclerosis is critical to treatment management because of the difference in natural history. Intensive medical treatment including blood pressure lowering medication reduces the risk of both primary and secondary vascular events in patients at risk. This review summarises recent data on blood pressure management in patients with carotid artery stenosis.

Background: New medical approaches to the autonomic nervous system, such as catheterbased renal denervation, have been introduced into clinical practice in the recent years for patients who have resistant hypertension. Objectives and Methods: We estimate the number of subjects in Japan who would benefit from renal denervation when this treatment is introduced into Japan, based on data from the Jichi Medical University clinical trials. We also discuss the logical basis of changing the formerly used primary endpoint, i.e., office BP, to 24-hr ambulatory BP in future clinical trials. Results: Among JAMP registry data, the total number of hypertensives was 5,858 and the patients who were prescribed ≥ 3 drugs including diuretics were 749. The poorly controlled hypertension rate was 32% in the group prescribed ≥ 3 drugs including diuretics and it constitutes 4.1% of the total hypertensive patients. We also analyzed the data of JMS ABPM cohort study wave 1 (811 patients). The hazard ratios (HRs) for each 10-mmHg increase in BP was 1.38 (95%CI 1.17–1.63, p<0.001) for 24-hr BP and 1.18 (95%CI 1.05–1.33, p=0.006) for office BP. However, the significance for office BP was lost once the 24-hr, daytime and nighttime ambulatory BP data were added to the covariates. Conclusion: The prevalence of resistant hypertensive patients among all of the hypertensive patients is 4.1%. Based on this prevalence, the number of resistant hypertensive individuals in Japan would be 1,870,000 patients. In future renal denervation clinical studies in Japan, we should set the primary endpoint as a 24-hr systolic BP reduction measured by ABPM.

Background: There are important differences in the lifestyle and cardiovascular disease risks between Asian and Western populations. The objective of this survey was to investigate the awareness of these factors in the practice of hypertension management among Asian physicians. Methods: General practitioners and specialists in Asia were surveyed by questionnaire with regard to their management of hypertension. Physicians attending international conferences or meetings on hypertension between March and May 2014 were asked to participate. Results: In their treatment of hypertensive patients, 87% of the 133 respondents said they considered the Asian lifestyle and region-specific characteristics of hypertension in their treatment decisions, while just less than 11% did not. Almost all physicians (92%) recognized the necessity for an Asian-specific guideline for the management of hypertension. For patients with diabetes, 37% and 59% of the respondents used target systolic blood pressure (SBP) levels of 140 mmHg and 130 mmHg, respectively; for elderly patients, 37% and 53% of respondents used target SBP levels of 140 and l50 mmHg, respectively. Forty-eight percent of Asian physicians used calcium channel blockers as the first-line choice of antihypertensive drug while 34% selected angiotensin II receptor blockers, 14% angiotensin converting enzyme inhibitors and 3% diuretics. Conclusion: Asian physicians consider that an Asian-specific guideline is needed for hypertension management in the Asian population.