Epigenetic mechanisms underlying renal derangement in hypertension and diabetes

• Project/Area Number: 24659410
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: FUJITA Toshiro 東京大学, 先端科学技術研究センター, 特任研究員、名誉教授 (10114125)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 糖尿病性腎症 / 高血圧 / 食塩 / エピジェネティクス / 糖尿病 / DNAメチル化

Research Abstract

Diabetes is often complicated with hypertension, but the underlying mechanisms have not been clarified. We investigated whether epigenetic derangement in the kidney underlies hypertension in diabetic model animals.
Because kidney is composed with multiple cell types, we sorted proximal tubule cells and investigated the differential DNA methylation status. In normal mice, DNA methylation of multiple genes including those involved in blood pressure regulation was selectively demethylated in proximal tubules. In db/db mice, diabetic mice with salt sensitive hypertension, aberrant DNA methylation and mRNA changes were detected in some of the genes related to blood pressure regulation. These results suggest that epigenetic abnormalities may underlie hypertension in diabetes.

Research Products

• [Journal Article] Mechanism of Salt-Sensitive Hypertension: Focus on Adrenal and Sympathetic Nervous Systems (2014)
  • Author(s): Fujita, T
  • Journal Title: J Am Soc Nephrol Volume: in press Issue: 6 Pages: 1148-1155
  • DOI: 10.1681/asn.2013121258
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. (2014)
  • Author(s): Jimbo, R., Kawakami-Mori, F., Mu, S., Hirohama, D., Majtan, B., Shimizu, Y., Yatomi, Y., Fukumoto, S., Fujita, T., and Shimosawa, T.
  • Journal Title: Kidney Int Volume: in press Issue: 5 Pages: 1103-1111
  • DOI: 10.1038/ki.2013.332
  • Peer Reviewed
• [Journal Article] Local Mineralocorticoid Receptor Activation and the Role of Rac1 in Obesity-Related Diabetic Kidney Disease. (2014)
  • Author(s): Yoshida S, Ishizawa K, Ayuzawa N, Ueda K, Takeuchi M, Kawarazaki W, Fujita T, Nagase M.
  • Journal Title: Nephron Exp Nephrol Volume: in press Issue: 1 Pages: 16-24
  • DOI: 10.1159/000358758
  • Peer Reviewed
• [Journal Article] Genome-wide analysis of murine renal distal convoluted tubular cells for the target genes of mineralocorticoid receptor (2014)
  • Author(s): Kohei Ueda, Katsunori Fujiki, Katsuhiko Shirahige, Celso E. Gomez-Sanchez, Toshiro Fujita, Masaomi Nangaku, Miki Nagase.
  • Journal Title: Biochemical and Biophysical Research Commnications Volume: 445 Issue: 1 Pages: 132-137
  • DOI: 10.1016/j.bbrc.2014.01.125
  • Peer Reviewed
• [Journal Article] Renin inhibition ameliorates renal damage through prominent suppression of both angiotensin I and II in human renin angiotensinogen transgenic mice with high salt loading (2014)
  • Author(s): Yoshida S, Ishizawa K, Ayuzawa N, Ueda K, Takeuchi M, Kawarazaki W, Fujita T, Nagase M.
  • Journal Title: Clin Exp Nephrol Volume: in press Issue: 4 Pages: 593-599
  • DOI: 10.1007/s10157-013-0893-6
  • Peer Reviewed
• [Journal Article] A novel link between Slc22a18 and fat accumulation revealed by a mutation in the spontaneously hypertensive rat. (2013)
  • Author(s): Yamamoto, T., Izumi-Yamamoto, K., Iizuka, Y., Shirota, M., Nagase, M., Fujita, T., and Gotoda, T.
  • Journal Title: Biochem Biophys Res Commun Volume: 440 Issue: 4 Pages: 521-526
  • DOI: 10.1016/j.bbrc.2013.09.096
  • Peer Reviewed
• [Journal Article] The role of CNS in salt-sensitive hypertension (2013)
  • Author(s): Fujita, M., and Fujita, T
  • Journal Title: Curr Hypertens Rep Volume: 15 Issue: 4 Pages: 390-394
  • DOI: 10.1007/s11906-013-0358-z
  • Peer Reviewed
• [Journal Article] Aberrant Rac1-mineralocorticoid receptor pathways in salt-sensitive hypertension (2013)
  • Author(s): Kawarazaki, W., and Fujita, T
  • Journal Title: Clin Exp Pharmacol Physiol Volume: 40 Issue: 12 Pages: 929-936
  • DOI: 10.1111/1440-1681.12177
  • Peer Reviewed
• [Journal Article] A useful method of identifying of miRNAs which can down-regulate Zeb-2 (2013)
  • Author(s): Shigeyoshi Oba, Takayuki Mizutani, Etsu Suzuki, Hiroaki Nishimatsu, Masao Takahashi, Yousuke Ogawa, Kenjiro Kimura, Yasunobu Hirata, and Toshiro Fujita
  • Journal Title: BMC Res Notes Volume: 6 Issue: 1 Pages: 1-8
  • DOI: 10.1186/1756-0500-6-470
  • Peer Reviewed
• [Journal Article] Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing oxidized LDL receptor. (2013)
  • Author(s): Ogura S, Shimosawa T, Mu SY, Sonobe T, Kawakami-Mori F, Wang H, Uetake y. Yoshida K, Yatomi Y, S hirai M, Fujita T.
  • Journal Title: Am J Physiol Heart and Circ Physiol Volume: 305(2) Issue: 2 Pages: H155-H162
  • DOI: 10.1152/ajpheart.00169.2012
  • Peer Reviewed
• [Journal Article] FRET-based sensor analysis reveals caveolae are spatially distinct Ca2+ stores in endothelial cells. (2013)
  • Author(s): Isshiki, M., Nishimoto, M., Mizuno, R., and Fujita, T.
  • Journal Title: Cell Calcium Volume: 54 Issue: 6 Pages: 395-403
  • DOI: 10.1016/j.ceca.2013.09.002
  • Peer Reviewed
• [Journal Article] The role of adrenomedullin in the renal NADPH oxidase and (pro)renin in diabetic mice. (2013)
  • Author(s): Hayashi, M., Tojo, A., Shimosawa, T., and Fujita, T.
  • Journal Title: J Diabetes Res Volume: - Pages: 134395-134395
  • DOI: 10.1155/2013/134395
  • Peer Reviewed
• [Journal Article] Role of Racl - mineralocorticoid receptor signalling in renal and cardiacdisease. (2013)
  • Author(s): Nagase M, et al.
  • Journal Title: Nat. Rev. Nephrol. Volume: 9 Issue: 2 Pages: 86-98
  • DOI: 10.1038/nrneph.2012.282
  • Peer Reviewed
• [Journal Article] Mineralocorticoid receptors in the pathophysiology of chronic kidney diseases and the metabolic syndrome (2012)
  • Author(s): Shibata S, Fujita T.
  • Journal Title: Mol Cell Endocrinol Volume: 350(2) Issue: 2 Pages: 273-80
  • DOI: 10.1016/j.mce.2011.07.018
  • Peer Reviewed
• [Journal Article] Pathophysiology of salt sensitivity hypertension. (2012)
  • Author(s): Ando K, Fujita T
  • Journal Title: Ann Med Volume: 44 Issue: sup1 Pages: S119-S126
  • DOI: 10.3109/07853890.2012.671538
  • Peer Reviewed
• [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] Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1 (2012)
  • Author(s): Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, Fujita T.
  • Journal Title: Hypertension Volume: 59 Issue: 2 Pages: 500-6
  • DOI: 10.1161/hypertensionaha.111.185520
  • Peer Reviewed
• [Journal Article] Angiotensin II- and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation (2012)
  • Author(s): Kawarazaki W, Nagase M, Yoshida S, Takeuchi M, Ihizawa N, Ueda K, Fujita T
  • Journal Title: J Am Soc Nephrol Volume: 23 Issue: 6 Pages: 997-1007
  • DOI: 10.1681/asn.2011070734
  • 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
• [Presentation] Interactions between Sodium and Potassium on blood pressure and cardiovascular disease (2014)
  • Author(s): Fujita T.
  • Organizer: at Asian Pacific Congress of Hypertension (APCH)
  • Place of Presentation: Cebu city, Philippines
  • Invited
• [Presentation] The Mechanism for Activation of Mineralocorticoid Receptor in the Heart and Kidney (2014)
  • Author(s): Fujita T.
  • Organizer: Gordon Research Conference"The Renin-Angiotensin System Beyond Angiotensin II"
  • Place of Presentation: Lucca (Barga), Italy(Keynote Lecture)
• [Presentation] The Mechanism for Activation of Mineralocorticoid Receptor in the Heart and Kidney (2014)
  • Author(s): Fujita T
  • Organizer: Gordon Research Conference “The Renin-Angiotensin System Beyond Angiotensin II”
  • Place of Presentation: Lucca (Barga), Italy
  • Invited
• [Presentation] Epigenetics in salt-sensitive hypertension (2013)
  • Author(s): Fujita T.
  • Organizer: at the 8th annual Winter Research Meeting on Translational Basic Science, European Society of cardiology
  • Place of Presentation: Les Diablerets- Switzerland
  • Invited
• [Presentation] Salt, obesity and hypertension (2013)
  • Author(s): Fujita T.
  • Organizer: at The 5th Pulse of Asia
  • Place of Presentation: Seol, Korea(Plenary Lecture)
• [Presentation] The kidney and hypertension : The pathogenesis of Salt-Sensitive Hypertension (2013)
  • Author(s): Fujita T.
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Hong Kong(Plenary Lecture)
• [Presentation] Mineralocorticoid Receptor (2013)
  • Author(s): Fujita T.
  • Organizer: at Cardiovascular Seminar"Fundamental Mechanisms of Hypertension", American Heart association (AHA)
  • Place of Presentation: Dallas, USA
  • Invited
• [Presentation] The Mechanism of salt-sensitive hypertension,salt, obesity and hypertension (2013)
  • Author(s): Fujita T.
  • Organizer: at Ruijin Hospital (Prof. Pingjin Gao, Shanghai Jiaotong University, School of Medicine),at the 7th Oriental Congress of cardiology(OCC)
  • Place of Presentation: Shanghai, China
• [Presentation] "Honorary Membership Award"and Lecture"The pathogenesis of Salt-sensitive hypertension" (2013)
  • Author(s): Fujita T.
  • Organizer: at Working group of kidney at ESH meeting
  • Place of Presentation: Milan on
• [Presentation] Chairperson at Basic and Clinical Science"Flipping the Switch : Small GTPases in CKD" (2013)
  • Author(s): Fujita T.
  • Organizer: at American Society of Nephrology (ASN)
  • Place of Presentation: Atlanta, USA
• [Presentation] Salt, obesity and hypertension (2013)
  • Author(s): Fujita T
  • Organizer: The 5th Pulse of Asia
  • Place of Presentation: Soel, Korea
  • Invited
• [Presentation] The pathogenesis of Salt-sensitive hypertension (2013)
  • Author(s): Fujita T
  • Organizer: Working group of kidney at ESH meeting
  • Place of Presentation: Milan, Italy
  • Invited
• [Presentation] The kidney and hypertension: The pathogenesis of Salt-Sensitive Hypertension (2013)
  • Author(s): Fujita T
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Hong Kong, China
  • Invited
• [Presentation] Epigenetics in salt-sensitive hypertension (2013)
  • Author(s): Fujita T
  • Organizer: 8th annual Winter Research Meeting on Translational Basic Science, European Society of Cardiology
  • Place of Presentation: Les Diablerets- Switzerland
  • Invited
• [Presentation] Activation of Rac1-mineralocorticoid pathway in proteinuric kidney disease (2012)
  • Author(s): Fujita T.
  • Organizer: at the 9th International Podocyte Conference
  • Place of Presentation: Miami, Florida USA
  • Invited
• [Presentation] The mechanism of salt-sensitive hypertension (2012)
  • Author(s): Fujita T.
  • Organizer: the 22nd European Society of Hypertension (ESH)
  • Place of Presentation: London, United Kingdom
  • Invited
• [Presentation] Role of Sympathetic nervous system in salt-sensitive hypertension (2012)
  • Author(s): Fujita T.
  • Organizer: at the satellite meeting of ISH 2012:"The neuropathophysiology of hypertension-an emerging therapeutic target"
  • Place of Presentation: Palm Cove, Queensland
  • Invited
• [Presentation] The mechanism of salt-sensitive hypertension (2012)
  • Author(s): Fujita T.
  • Organizer: at the 24th Scientific Meeting of the International Society of Hypertension (ISH)
  • Place of Presentation: Sydney(Plenary lecture)
• [Presentation] Rac1-MR activation in salt-sensitive hypertension (2012)
  • Author(s): Fujita T.
  • Organizer: at the satellite meeting of ISH 2012:"Aldosterone and salt : Heart and kidney"
  • Place of Presentation: Palm Cove Queensland
  • Invited
• [Presentation] Activation of Rac1-MR pathway in salt-sensitive hypertension (2012)
  • Author(s): Fujita T.
  • Organizer: at the 45th annual meeting of American Society of Nephrology
  • Place of Presentation: San Diego, US(Symposium lecture)
• [Presentation] Role of Rac1-MR pathway in salt-sensitive hypertension (2012)
  • Author(s): Fujita T.
  • Organizer: at European Section of Aldosterone Council
  • Place of Presentation: Hannover, Germany
  • Invited
• [Presentation] Activation of Rac1-mineralocorticoid pathway in proteinuric kidney disease (2012)
  • Author(s): Fujita T
  • Organizer: 9th International Podocyte Conference
  • Place of Presentation: Miami, USA
  • Invited
• [Presentation] The mechanism of salt-sensitive hypertension (2012)
  • Author(s): Fujita T
  • Organizer: 22nd European Society of Hypertension (ESH)
  • Place of Presentation: London, United Kingdom
  • Invited
• [Presentation] The mechanism of salt-sensitive hypertension (2012)
  • Author(s): Fujita T
  • Organizer: 24th Scientific Meeting of the International Society of Hypertension (ISH)
  • Place of Presentation: Sydbey, Australia
  • Invited
• [Presentation] Activation of Rac1-MR pathway in salt-sensitive hypertension (2012)
  • Author(s): Fujita T
  • Organizer: 45th annual meeting of American Society of Nephrology
  • Place of Presentation: San Diego, USA
  • Invited
• [Presentation] Role of Rac1-MR pathway in salt-sensitive hypertension (2012)
  • Author(s): Fujita T
  • Organizer: European Section of Aldosterone Council
  • Place of Presentation: Hannover, Germany
  • Invited
• [Remarks]
  • URL: http://www.c-epi.rcast.u-tokyo.ac.jp/