2013 Fiscal Year Final Research Report
The mechanism for activation of aldosterone/mineralocorticoid receptor in life style-related diseases
| Project/Area Number |
21229012
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Endocrinology
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| Research Institution | The University of Tokyo |
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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)
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| Co-Investigator(Kenkyū-buntansha) |
NAGASE Miki 順天堂大学, 医学部解剖学, 准教授 (60302733)
ANDO Katsuyuki 東京大学, 医学部附属病院, 特任准教授 (60184313)
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| Co-Investigator(Renkei-kenkyūsha) |
TANAKA Hirotoshi 東京大学, 医科学研究所, 教授 (00171794)
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| Project Period (FY) |
2009-05-11 – 2014-03-31
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| Keywords | アルドステロン / 食塩感受性高血圧 / エピジェネティクス / 交感神経 / 核内受容体 |
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| Research Abstract |
We previously reported the novel mechanism of mineralocorticoid receptor (MR) activation by Rac1 (Nat Med 2008). In this project, we found that activation of Rac1-MR pathway, induced by reactive oxygen species, causes injury of the heart, kidney and brain. Rac1-MR activation in glomerular podocytes and renal tubular cells causes glomerular damage and salt-sensitive hypertension (JCI 2011), respectively.
We also found that activation of glucocorticoid receptor (GR), another nuclear receptor, stimulates renal sympathetic activity resulting in activation of GR-WNK4-NCC pathway by changing histone modulation (Nat Med 2011). It suggests that epigenetic modulation is intimately involved in the MR and GR activation with sodium reabsorption in the different tubular sites.
Taken together, we identified the two novel pathways of MR- and GR-activation for the development of salt-sensitive hypertension, leading to the clue of epigenetic regulation of organ damage in metabolic syndrome.
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[Journal Article] Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension2011
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
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Journal Title
Nat Med
Volume: 17
Pages: 573-580
Peer Reviewed
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[Journal Article] Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway2011
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
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Journal Title
J Clin Invest
Volume: 121
Pages: 3233-3243
Peer Reviewed
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[Journal Article] Common variation in GPC5 is associated with acquired nephrotic syndrome2011
Author(s)
Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T, Watanabe T, Nishida N, Mabuchi A, Takahashi A, Kubo M, Maeda S, Nakamura Y, Noiri E
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Journal Title
Nat Genet
Volume: 43(5)
Pages: 459-63
Peer Reviewed
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[Journal Article] Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling2011
Author(s)
Endo Y, Suzuki M, Yamada H, Horita S, Kunimi M, Yamazaki O, Shirai A, Nakamura M, Iso-O N, Li Y, Hara M, Tsukamoto K, Moriyama N, Kudo A, Kawakami H, Yamauchi T, Kubota N, Kadowaki T, Kume H, Enomoto Y, Homma Y, Seki G, Fujita T
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Journal Title
Cell Metab
Volume: 13(5)
Pages: 550-61
Peer Reviewed
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[Journal Article] siRNA-based therapy for glomerulonephritis2010
Author(s)
Shimizu H, Hori Y, Kaname S, Yamada K, Nishiyama N, Matsumoto S, Miyata K, Oba M, Yamada A, Kataoka K, Fujita T
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Journal Title
J Am Soc Nephrol
Volume: 21(4)
Pages: 622-33
Peer Reviewed
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