Report of the National Heart, Lung, and Blood Institute Working Group on Epigenetics and Hypertension

Cowley, Allen W.; Nadeau, Joseph H.; Baccarelli, Andrea; Berecek, Kathleen H.; Fornage, Myriam; Gibbons, Gary H.; Harrison, David G.; Liang, Mingyu; Nathanielsz, Peter W.; O’Connor, Daniel T.; Ordovas, José M.; Peng, Weiqun; Soares, Marcelo B.; Szyf, Moshe; Tolunay, Hatice; Wood, Katherine C.; Zhao, Keji; Galis, Zorina S.

doi:10.1161/hypertensionaha.111.190116

Cited by 94 publications

(71 citation statements)

References 54 publications

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“…37 These observations have obscured the question of how much physical factors related to the elevation of renal perfusion pressure (RPP) actually contribute to renal injury in hypertension. This issue presents a great challenge, given the difficulty in sustaining a chronic increase of arterial pressure without concomitantly altering the systemic neurohormonal factors, such as circulating levels of angiotensin II, known to cause tissue injury independent of elevated arterial pressure.…”

Section: B-enac Expression In Servocontrolled Ratsmentioning

confidence: 99%

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na + absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na + transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a lowsalt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na + reabsorption in the collecting duct and the development of hypertension. More than 76 million American adults have high BP 1 and the likelihood of developing hypertension significantly increases with age. Nearly 40% of African Americans aged .20 years exhibit hypertension and nearly 70% of these individuals have a form of hypertension that is highly sensitive to salt intake. A reduced ability to maintain sodium homeostasis and normal levels of arterial pressure is a hallmark of all forms of hypertension. 2 In the kidney, discretionary Na + reabsorption in response to endocrine input to the aldosterone-sensitive distal nephron (ASDN) is a determinant of the pressurenatriuresis relationship, which is of fundamental importance in the long-term control of arterial pressure. 2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis. [5][6][7] The EGF and related hormones are multipotent agents [8][9][10][11] involved in regulation of various renal

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Section: B-enac Expression In Servocontrolled Ratsmentioning

confidence: 99%

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

Self Cite

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“…Differences from control (*) and DOCA salt (?). Values are expressed as mean ± SEM (n = [8][9][10][11][12][13][14][15] reported [5][6][7]. In our study, DOCA salt-induced hypertension was prevented by resveratrol but, blood pressure of the normal animals was not affected.…”

Section: Discussionmentioning

confidence: 63%

“…Resveratrol is a natural polyphenol present in plants and various human foods. It has been demonstrated that resveratrol has several pharmacological effects, including anti-oxidant, anti-atherogenic, anti-inflammatory, anti-platelet, anti-fungal, antiaging and anti-cancer properties [8]. In the cardiovascular system, resveratrol is able to decrease contractions in the cardiac and vascular smooth muscle [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

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Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension

et al. 2014

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Hypertension is a risk factor for the cardiovascular diseases. Although, several drugs are used to treat hypertension, the success of the antihypertensive therapy is limited. Resveratrol decreases blood pressure in animal models of hypertension. This study researched the mechanisms behind the effects of resveratrol on hypertension. Hypertension was induced by using the deoxycorticosterone acetate (DOCA)-induced (15 mg/kg twice per week, subcutaneously) salt-sensitive hypertension model of Wistar rats. Hypertension caused a decrease in endotheliumdependent relaxations of the isolated thoracic aorta. Resveratrol treatment (50 mg/l in drinking water) prevented DOCA salt-induced hypertension, but did not improve endothelial dysfunction. Plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulfide (H 2 S) levels were not changed by DOCA salt application. However, treatment of resveratrol significantly decreased ADMA and increased TAC and H 2 S levels. NO level in circulation was not significantly changed by resveratrol. DOCA salt application and resveratrol treatment also caused an alteration in the epigenetic modification of vessels. Staining pattern of histone 3 lysine 27 methylation (H3K27me3) in the aorta and renal artery sections was changed. These results show that preventive effect of resveratrol on DOCA salt-induced hypertension might due to its action on the production of some blood biomarkers and the epigenetic modification of vessels that would focus upon new aspect of hypertension prevention and treatment.

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“…Они обу-словлены структурными адаптациями областей хромосом и уве-ковечивают состояния их измененной активности. Эксперимен-тальные исследования свидетельствуют о том, что эпигенетиче-ские изменения могут возникать на протяжении всей жизни -от эмбриональной стадии и до старости -как результат развития или физиологических процессов, влияния окружения или, что хотелось бы подчеркнуть, случайного события [17].…”

Section: терапевтический архив 1 2015unclassified

Arterial hypertension: An expanding pathogenic continuum and therapeutic limitations

2015

Ter. arkh.

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ЛЕКЦИЯОписание первопричин артериальной гипертонии (АГ) по-прежнему распадается на области «света» и «тени». Первая охва-тывает симптоматические (вторичные) АГ, поскольку понима-ние их патогенеза представляется ясным. К «теневой» же отно-сится эссенциальная АГ (ЭАГ), этиология которой не раскрыта полностью. Проявления вторичных АГ при разных нарушениях, как и вовлечение различных систем организма при ЭАГ и факто-ры риска (ФР), связанные с нею, несомненно, свидетельствуют о том, что существует множество путей к повышению артериаль-ного давления (АД). Это впервые отражено в мозаичной концеп-ции ЭАГ, сформулированной в середине прошлого столетия I. Page [1], которая развивалась параллельно с другими моделями. В основе последних лежала идея о ведущей роли в развитии ЭАГ нервной системы и почек. Согласно мозаичной теории возник-новение ЭАГ обусловлено переплетением разных факторов, на-пример наследственности, окружения, адаптации, механиче-ских, нервных и гормональных нарушений. В последние десяти-летия показано, что ими перечень патогенетических факторов, обусловливающих повышение АД, не исчерпывается, а суще-ствующий арсенал антигипертензивных средств, отражающий классические представления о патогенезе АГ, не обеспечивает терапевтический эффект при резистентной форме АГ. Стреми-тельное развитие научных технологий позволило выявить новые клеточные и молекулярные уровни патогенеза ЭАГ и признать возможность развития самых разных его сценариев, инициируе-мых как отдельными пусковыми факторами, так и их комбина-циями, которые можно рассматривать в контексте патогенетиче-ского континуума (ПГК).В общем случае ПГК можно рассматривать как совокуп-ность возникающих под влиянием внешних и внутренних факто-ров нарушений в организме, изменяющих его глобальный регу-Контактная информация: Харченко Евгений Петрович -д.б.н., в.н.с. лаб. нейрофизиологии ребенка; e-mail: neuro.children@mail.ru АннотацияРассматриваются роль иммунной системы, стресса эндоплазматической сети, метаболической дисрегуляции и эпигенетических механизмов в патогенезе эссенциальной артериальной гипертонии, а также ограниченные возможности терапии существующими антигипертензивными препаратами. Ключевые слова: эссенциальная артериальная гипертония, патогенез, иммунная система, эндоплазматическая сеть, эпи-генетика, терапия.The paper considers the role of the immune system, endoplasmic network stress, metabolic dysregulation, and epigenetic mechanisms in the pathogenesis of essential hypertension, as well as the limited possibilities of therapy with existing antihypertensive agents. Key words: essential hypertension, pathogenesis, immune system, endoplasmic network, epigenetics, therapy.АГ -артериальная гипертония АД -артериальное давление ИЛ -интерлейкин ИС -иммунная система ПГК -патогенетический континуум РК -регуляторный континуум СД -сахарный диабет ССЗ -сердечно-сосудистые заболевания ФР -фактор риска ЭАГ -эссенциальная АГ ЭС -эндоплазматическая сеть α-ФНО -α-фактор некроза опухоли ляторный континуум (РК), охватывающий все системы регуля-ции и реализующийс...

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Report of the National Heart, Lung, and Blood Institute Working Group on Epigenetics and Hypertension

Cited by 94 publications

References 54 publications

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension

Arterial hypertension: An expanding pathogenic continuum and therapeutic limitations

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