Molecular Mechanism of Cardiorenal Syndrome through Flt-1 system: Involvement of novel LncRNA

• Project/Area Number: 16H05301
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nara Medical University
• Principal Investigator: Yoshihiko Saito 奈良県立医科大学, 医学部, 教授 (30250260)
• Co-Investigator(Kenkyū-buntansha): 熊澤 拓也 奈良県立医科大学, 医学部, 研究員 (10745441) ; 尾上 健児 奈良県立医科大学, 医学部, 学内講師 (90510173)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2016: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: sFlt-1 / CKD / LncRNA / 慢性腎臓病 / 心不全 / 心腎連関 / Lnc RNA / Flt-1 / 生体生命情報学 / 核酸 / シグナル伝達 / 循環器・高血圧 / PLGF / non-cording RNA / 内科

Outline of Final Research Achievements

Molecular mechanism of cardio-renal connection is unclear. In this study, we disclosed the upregulation of placental growth factor (PLGF) and down-regulation of its endogenous antagonist, soluble fms-like tyrosine kinase-1(sFlt-1). Consequently PLGF/Flt-1 signaling is activated in chronic kidney diseases. Mice specifically lacking sFlt-1 (sFlt-1 KO) with transverse aortic constriction (TAC), showed poorer prognosis than wild type mice with TAC. Ventricular hypertrophy and interstitial fibrosis were worsened in sFlt-1 KO, accompanied by MCP-1 upregulation. Using the microarray technique, we identified a novel long non-cording RNA X which specifically down-regulated in the ventricle of sFlt-1 KO with TAC. It directly binds to MEK and ERK phosphorylation. The treatment with AAV9 vector carrying shLnc RNA X inhibited Lnc RNA X in WT mice and worsened hypertrophy and cardiac function. MCP-1 and the Lnc RNA X would be possible drug discovery targets for cardiorenal connection.

Academic Significance and Societal Importance of the Research Achievements

心腎連関は、よく知られた現象であるが、過去には、血行動態的に理解されていたが、その基盤に存在する分子機序は不明な点が多かった。しかし、今回、腎機能が低下すると、尿毒症毒素や参加ストレスを介して、血管内皮からのPLGFの産生が増加し、その内因性の拮抗物質である可溶性Flt-1の産生が低下した結果、心不全の発症につながることを実験的に証明した。また、Flt-1の下流に存在するMCP-1の関与と、新規に発見したnon-cording RNAがMEKを阻害する作用を介して介在していることを世界で初めて提唱した。

Research Products

• [Journal Article] Prognostic Value of Urinary Neutrophil Gelatinase-Associated Lipocalin on the First Day of Admission for Adverse Events in Patients With Acute Decompensated Heart Failure. (2017)
  • Author(s): Nakada Y, Kawakami R, Matsui M, Ueda T, Nakano T, Takitsume A, Nakagawa N, Nishida T, Onoue K, Soeda T, Okayama S, Watanabe M, Kawata H, Okura H, Saito Y.
  • Journal Title: J Am Heart Assoc. Volume: 6 Issue: 5
  • DOI: 10.1161/jaha.116.004582
  • Peer Reviewed / Open Access
• [Journal Article] Suppressed Production of Soluble Fms-like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure. (2016)
  • Author(s): Seno A, Takeda Y, Matsui M, Okuda A, Nakano T, Yasuki N, Kumasawa T, Hitoshi N, Nishida T, Onoue K, Somekawa S, Watanabe M, Kawata H, Kawakami R, Okura H, Uemura S, Saito Y.
  • Journal Title: Hypertension. Volume: 68 Issue: 3 Pages: 678-687
  • DOI: 10.1161/hypertensionaha.116.07371
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A Novel Long Noncoding RNA LncX Suppresses the Progression of Cardio-renal Syndrome. (2018)
  • Author(s): Kumazawa T, Nakagawa H, Nakada Y, Nakano T, Onoue K, Saito Y.
  • Organizer: The 1st JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] Oral Carbon Absorbent Protects the Progression of Atherosclerosis via Preserving sFlt-1 Expression. (2018)
  • Author(s): Nakada Y, Onoue K, Kumazawa T, Ishihara S, Kamon D, Nakano T, Nakagawa H, Okura H, Saito Y.
  • Organizer: The 1st JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] A novel long noncoding RNA protects the heart from cardiorenal syndrome type4. (2017)
  • Author(s): KumazawaT, Saito Y.
  • Organizer: 第34回国際心臓研究学会日本部会（ISHR）
• [Presentation] Placental Growth Factor as a Predictor of Long-term Outcome in Patients with Acute Decompensated Heart Failure From the NARA-HF study. (2016)
  • Author(s): Nakada Y, KawakamiR, Nakano T, Nakagawa H, Ueda T, Onoue K, Okura H, Saito Y.
  • Organizer: 第３３回国際心臓研究学会日本部会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-16
• [Presentation] Epidemiological Features and Prognosis of Acute Decompensated Heart Failure: a Comparison between NARA-HF study and Asian Prospective Cohort Studies. (2016)
  • Author(s): Kawakami R, Saito Y.
  • Organizer: 第２０回日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
  • Invited
• [Remarks] http://www.naramed-u.ac.jp/~1int/
• [Remarks] http://www.naramed-u.ac.jp/~1int/index.html
• [Remarks] 奈良県立医科大学 第１内科学教室ホームページ
  • URL: http://www.naramed-u.ac.jp/~1int/index.html