Mechanisms and diagnosis of salt-sensitive hypertension in view point of epigenetics

• Project/Area Number: 23591213
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: SHIMOSAWA Tatsuo 東京大学, 医学部附属病院, 講師 (90231365)
• Co-Investigator(Renkei-kenkyūsha): ANDO Katsuyuki 東京大学, 医学部附属病院, 特任准教授 (60184313)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 高血圧学 / エピゲノム修飾 / マイクロRNA / アルドステロン / 食塩感受性 / 腎障害 / 食塩感受性高血圧 / HDAC2 / 酸化ストレス / microRNA

Research Abstract

The pathophysiology of salt-sensitive hypertension and its related organ damage were investigated in view point of epigenetic modifications. We have reported histone modification leads to salt-sensitive hypertension and in addition to it, we revealed that micro RNA regulates several genes which are regulators for oxidative stress and cause organ damages. And microRNA can be used for a tool to treat or prevent organ damages in salt-sensitive hypertension.
In human study, we preliminary investigated that cells in urine can be used to detect tubular function and may be useful to diagnose salt-sensitivity.

Research Products

• [Journal Article] 食塩感受性高血圧におけるβ_2アドレナリン作動性受容体とナトリウム再吸収調節系(WNK4経路) (2013)
  • Author(s): 下澤達雄
  • Journal Title: 生体の科学 Volume: 64 Pages: 386-387
• [Journal Article] Salt, the renin–angiotensin–aldosterone system and resistant hypertension (2013)
  • Author(s): Shimosawa T
  • Journal Title: Hypertension Res Volume: 36 Pages: 657-660
• [Journal Article] 高血圧と臓器障害の病因解明と診断法開発 (2013)
  • Author(s): 下澤達雄
  • Journal Title: 臨床病理 Volume: 61 Pages: 263-270
  • NAID: 10031171354
• [Journal Article] Adrenomedullin Haploinsufficiency Predisposes to Secondary Lymphedema. (2013)
  • Author(s): Nikitenko LL, Shimosawa T, Henderson S, Mäkinen T, Shimosawa H, Qureshi U, Pedley RB, Rees MC, Fujita T, Boshoff C.
  • Journal Title: J Invest Dermatol Volume: in press Issue: 7 Pages: 1768-1776
  • DOI: 10.1038/jid.2013.47
  • Peer Reviewed
• [Journal Article] Adrenomedullin in peritoneal effluent expressed by peritoneal mesothelial cells. (2013)
  • Author(s): Kono R, Kanozawa K, Shimosawa T, Tayama Y, Matsuda A, Hasegawa H, Mitarai T.
  • Journal Title: Clin Exp Nephrol Volume: in press
  • Peer Reviewed
• [Journal Article] NADPH oxidase-mediated Rac1 GTP activity is necessary for non-genomic actions of the mineralocorticoid receptor in the CA1 region of the rat hippocampus (2012)
  • Author(s): Kawakami- Mori F, Shimosawa T, Mu S, Wang H, Ogura S, Yatomi Y, Fujita T
  • Journal Title: Am J Physiol Endoc Metab Volume: 302
• [Journal Article] The Kidney and Hypertension : Pathogenesis of Salt-Sensitive Hypertension (2012)
  • Author(s): Shimosawa T, Shengyu M, Shibata S, Fujita T
  • Journal Title: Curr Hypertens Rep Volume: 14 Pages: 468-472
• [Journal Article] 食塩感受性の個人差のメカニズム-その遺伝的背景- (2012)
  • Author(s): 下澤達雄,穆勝宇,藤田敏郎
  • Journal Title: Medical Practice Volume: 29 Pages: 510-512
• [Journal Article] 食塩感受性高血圧におけるエピゲノム制御 (2012)
  • Author(s): 下澤達雄,穆勝宇,藤田敏郎
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 34 Pages: 347-352
  • NAID: 40019328758
• [Journal Article] 食塩感受性の分子生物学的機序 (2012)
  • Author(s): 下澤達雄
  • Journal Title: Progress in Medicine Volume: 32 Pages: 1020-1024
• [Journal Article] 食塩感受性高血圧の発症メカニズム (2012)
  • Author(s): 下澤達雄,藤田敏郎
  • Journal Title: 医学のあゆみ-高血圧のすべて2012 Volume: 241 Pages: 961-965
• [Journal Article] メタボリックシンドロームにおける食塩感受性高血圧と交感神経のかかわりWNKの関与 (2012)
  • Author(s): 下澤達雄
  • Journal Title: Angiotensin Research Volume: 9 Pages: 140-143
• [Journal Article] 臨床検査から病状を把握し,予後を予測するには尿検査の立場から (2012)
  • Author(s): 下澤達雄
  • Journal Title: 日本未病システム学会雑誌 Volume: 18 Pages: 99-103
• [Journal Article] The kidney and hypertension: pathogenesis of salt-sensitive hypertension (2012)
  • Author(s): Shimosawa T, Mu S, Shibata S, Fujita T
  • Journal Title: Curr Hypertens Rep Volume: 14 Issue: 5 Pages: 468-472
  • DOI: 10.1007/s11906-012-0284-5
  • Peer Reviewed
• [Journal Article] NADPH oxidase-mediated Rac1 GTP activity is necessary for nongenomic actions of the mineralocorticoid receptor in the CA1 region of the rat hippocampus (2012)
  • Author(s): Kawakami-Mori F, Shimosawa T, Mu S, Wang H, Ogura S, Yatomi Y, Fujita T.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302 Issue: 4 Pages: E425-E432
  • DOI: 10.1152/ajpendo.00227.2011
  • Peer Reviewed
• [Journal Article] Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans (2012)
  • Author(s): Hasegawa Y, Fujita T, et al.
  • Journal Title: Circulation Volume: 125 Issue: 9 Pages: 1122-1133
  • DOI: 10.1161/circulationaha.111.054346
  • Peer Reviewed
• [Journal Article] Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rats (2012)
  • Author(s): Kegeyama Y
  • Journal Title: Hepatology Volume: 56 Issue: 4 Pages: 1427-1438
  • DOI: 10.1002/hep.25780
  • Peer Reviewed
• [Journal Article] Function of adrenomedullin in inflammatory response of liver against LPS-induced endotoxemia. (2012)
  • Author(s): Saito R, Shimosawa T, Ogihara T, Maruyama N, Fujita T, Okamura N, Nakahara K.
  • Journal Title: APMIS Volume: 120 Issue: 9 Pages: 706-711
  • DOI: 10.1111/j.1600-0463.2012.02892.x
  • Peer Reviewed
• [Journal Article] Importance of endothelial NF-κB signaling in vascular remodeling and aortic aneurysm formation (2012)
  • Author(s): Saito T, Hasegawa Y, Ishigaki Y, Yamada T, Gao J, Imai J, Uno K, Kaneko K, Ogihara T, Shimosawa T, Asano T, Fujita T, Oka Y, Katagiri H.
  • Journal Title: Cardiovascular Research Volume: 97(1) Issue: 1 Pages: 106-114
  • DOI: 10.1093/cvr/cvs298
  • Peer Reviewed
• [Journal Article] 食塩感受性の個人差のメカニズム－その遺伝的背景－ (2012)
  • Author(s): 下澤達雄, 穆勝宇, 藤田敏郎
  • Journal Title: Medical Practice Volume: 29 Pages: 510-512
• [Journal Article] Epigenetic modulation of the renalβ-adrenergic-WNK4 pathway in salt-sensitive hypertension (2011)
  • Author(s): Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F, Marumo T, Yatomi Y, Geller DS, Tanaka H, Fujita T
  • Journal Title: Nat Med Volume: 17 Pages: 573-580
• [Journal Article] Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway (2011)
  • Author(s): Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, Kawarazaki W, Takeuchi M, Ayusawa N, Miyoshi J, Takai Y, Ishikawa A, Shimosawa T, Ando K, Nagase M, Fujita T
  • Journal Title: J Clin Invest Volume: 121 Pages: 3233-3243
• [Journal Article] Geller DS, Tanaka H, Fujita T Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. (2011)
  • Author(s): Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F, Marumo T, Yatomi Y
  • Journal Title: Nat Med.2011 Volume: 17(5) Issue: 5 Pages: 573-80
  • DOI: 10.1038/nm.2337
  • Peer Reviewed
• [Journal Article] Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. (2011)
  • Author(s): Shibata, S. et al.
  • Journal Title: J Clin Invest. Volume: 121 Issue: 8 Pages: 3233-3243
  • DOI: 10.1172/jci43124
  • Peer Reviewed
• [Presentation] 急性食塩負荷時の自律神経の変化 (2013)
  • Author(s): 下澤達雄,広浜大五郎,小倉彩世子,森典子,神保りか, Reheman Latapati,上竹勇三郎
  • Organizer: 第二回臨床高血圧フォーラム
  • Place of Presentation: 東京
• [Presentation] 妊娠時ストレスが胎児の発達後血圧に与える影響 (2013)
  • Author(s): 森典子,神保りか,広浜大五郎, Reheman Latapati,小倉彩世子,渡辺大輔,安藤孝,関康史,吉田尚弘,森本聡,市原淳弘,下澤達雄
  • Organizer: 第36回日本高血圧学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 急性食塩負荷時の交感神経活動の変化LF/HFでの評価 (2013)
  • Author(s): 下澤達雄,小倉彩世子,宿谷賢一,田中雅美,矢冨裕
  • Organizer: 第60回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸
• [Presentation] AngII,高食塩負荷モデルによる腎線維化に対するmicroRNA導入による改善効果 (2012)
  • Author(s): 森典子,下澤達雄,広浜大五郎,神保りか,穆勝宇,藤田敏郎
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 名古屋
• [Presentation] アンジオテンシンによる腎線維化障害へのmiR導入によるシグナル変化の検討 (2012)
  • Author(s): 森典子,神保りか,広浜大五郎,穆勝宇,藤田敏郎,下澤達雄
  • Organizer: 第16回日本心血管内分泌代謝学会
  • Place of Presentation: 東京
• [Presentation] AngII,高食塩負荷モデル による腎線維化に対するmicroRNA導入による改善効果. (2012)
  • Author(s): 森典子, 下澤達雄, 広浜大五郎, 神保りか, 穆勝宇, 藤田敏郎
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 名古屋
• [Presentation] Micro RNA29A recruitment ameliorates fibrosis induced by angiotensin II via RAC1 modulation. (2012)
  • Author(s): Mori F, Shimosawa T, Hirohama D, Jimbo R, Mu S, Fujita T.
  • Organizer: The 24th Scientific meeting of the International Society of Hypertension,
  • Place of Presentation: シドニー、オーストラリア
• [Presentation] Renalβ-adrenergic-stimulation-induced salt sensitive hyper-tension,interaction between WNK4 and glucocorticoid receptor (2011)
  • Author(s): Shengyu Mu, Tatsuo Shimosawa, Sayoko Ogura, Hong Wang, Yuzaburo Uetake, Fumiko Mori, Rika Jimbo, Yutaka Yatomi, David S Geller, Hirotoshi Tanaka, Toshiro Fujita
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] UUOモデルにおけるmicroRNAの変化および治療効果 (2011)
  • Author(s): 森典子,下澤達雄,神保りか,穆勝宇,上竹勇三郎,藤田敏郎
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Epigenetic Modulation of the Renalβ-adrenergic-WNK4Pathway in Salt-sensitive Hypertension (2011)
  • Author(s): Shengyu Mu, Tatsuo Shimosawa, Sayoko Ogura, Hong Wang, Yuzaburo Uetake, Fumiko Mori, Toshiro Fujita
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
• [Presentation] 食塩感受性高血圧の発生機序:腎β2受容体‐WNK4の役割とEpigenetic調節 (2011)
  • Author(s): 穆勝宇,下澤達雄,小倉彩世子,王紅,上竹勇三郎,森典子,矢冨裕,藤田敏郎
  • Organizer: 第15回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 生活習慣病の発症にかかわるヒストンアセチル化 (2011)
  • Author(s): 下澤達雄, 穆勝宇, 森典子, 上竹勇三郎, 史安男, 神保りか, レーマンラタパティ, 広浜大五郎, 藤田敏郎
  • Organizer: 日本内分泌学会(招待講演)
  • Place of Presentation: 神戸
• [Presentation] 食塩感受性メカニズムと治療戦略 (2011)
  • Author(s): 下澤達雄
  • Organizer: 日本臨床栄養学会(招待講演)
  • Place of Presentation: 東京
• [Presentation] 生活習慣病エピジェネティクスからの創薬 (2011)
  • Author(s): 下澤達雄, 穆勝宇, 藤田敏郎
  • Organizer: 日本臨床薬理学会(招待講演)
  • Place of Presentation: 浜松
• [Presentation] 食塩感受性高血圧の発生機序：腎β2受容体‐WNK4の役割とEpigenetic調節
  • Author(s): 穆勝宇, 下澤達雄, 小倉彩世子, 王紅, 上竹勇三郎, 森典子, 矢冨裕, 藤田敏郎
  • Organizer: 日本心血管内分泌代謝学会
  • Place of Presentation: 大阪
• [Presentation] Epigenetic Modulation of the Renal b-adrenergic-WNK4Pathway in Salt-sensitive Hypertension.
  • Author(s): Shengyu Mu, Tatsuo Shimosawa, Sayoko Ogura, Hong Wang, Yuzaburo Uetake, Fumiko Mori, Toshiro Fujita.
  • Organizer: 日本高血圧学会
  • Place of Presentation: 宇都宮
• [Book] Clinical nephrology全身性疾患と腎障害.食塩感受性高血圧の発症機序. Annual Review 2013腎臓.(富野康日己,柏原直樹,成田一衛編) (2013)
  • Author(s): 下澤達雄 (分担)
  • Publisher: 中外医学社(東京)
• [Book] 内分泌基礎分野での進歩.食塩感受性高血圧のエピジェネティクス. Annual Review 2013糖尿病・代謝・内分泌.(寺内康夫,伊藤裕,石橋俊編) (2013)
  • Author(s): 下澤達雄 (分担)
  • Publisher: 中外医学社(東京)
• [Book] Clinical nephrology 全身性疾患と腎障害. 食塩感受性高血圧の発症機序. Annual Review 2013腎臓. (2013)
  • Author(s): 下澤達雄
  • Total Pages: 3
  • Publisher: 中外医学社(東京)
• [Book] 高血圧・肺高血圧. 食塩感受性高血圧の分子機構. Annual Review 2013循環器.(小室一成,佐地勉,坂田隆造,赤阪隆史編) (2013)
  • Author(s): 下澤達雄
  • Total Pages: 4
  • Publisher: 中外医学社(東京)
• [Book] 内分泌 基礎分野での進歩. 食塩感受性高血圧のエピジェネティクス. Annual Review 2013糖尿病・代謝・内分泌.(寺内康夫,伊藤裕,石橋俊編) (2013)
  • Author(s): 下澤達雄
  • Total Pages: 4
  • Publisher: 中外医学社(東京)
• [Book] Oxidative stress in multiple organ damage in hypertension,diabetes and CKD,mechanisms and new therapeutic possibilities(Oxidative Stress and Diseases.Croatia) (2012)
  • Author(s): Shimosawa T, Kameko T, Qingyou X, Miyamoto Y, Shengyu M, Wang H,Ogura S, Jimbo R, Majtan B, Uetake Y, Hirohama D, Kawakami-Mori F, Fujita T(Volodymyr I. Lushchak, Dmytro V.Gospodaryov. Ed.)
• [Book] Oxidative stress in multiple organ damage in hypertension,diabetes and CKD,mechanisms and new therapeutic possibilities. In Volodymyr I. Lushchak, Dmytro V.Gospodaryov. ed. Oxidative Stress and Diseases. (2012)
  • Author(s): Shimosawa T,Kameko T,Qingyou X,Miyamoto Y, Shengyu M, Wang H,Ogura S,Jimbo R,Majtan B,Uetake Y,Hirohama D, Kawakami-Mori F,Fujita T
  • Total Pages: 13
  • Publisher: Intech, Croatina