2018 Fiscal Year Final Research Report
Molecular Mechanism of Cardiorenal Syndrome through Flt-1 system: Involvement of novel LncRNA
| Project/Area Number |
16H05301
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cardiovascular medicine
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| Research Institution | Nara Medical University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | sFlt-1 / CKD / LncRNA |
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| 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.
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| Free Research Field |
循環器内科学
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| 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。
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