2022 Fiscal Year Final Research Report
Functional analysis of renal tubule-derived semaphorin 3C in the development of cardiorenal syndrome
| Project/Area Number |
20K08486
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Yamagata University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
大瀧 陽一郎 山形大学, 医学部, 助教 (80732693)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | Semaphorin 3C / Cardio-renal syndrome / Wnt/β catenin signaling |
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| Outline of Final Research Achievements |
Cardiorenal syndrome (CRS) is associated with a high mortality rate. The mechanism underlying CRS has not yet been fully elucidated. Semaphorin 3C (SEMA3C) plays an important role in the development of the heart and kidney. The aim of this study was to examine the role of SEMA3C in CRS development. We generated tamoxifen-inducible proximal tubule-specific SEMA3C knockout mice (PT-SEMA3C KO). PT-SEMA3C KO mice showed exacerbated cardiac hypertrophy induced by TAC and had a lower survival rate than their wild-type littermates. RNA sequencing of heart tissue revealed enhanced Wnt/β-catenin signaling in PT-SEMA3C KO mice compared to wild-type littermates. Plasma SEMA3C levels were measured in 155 consecutive patients with heart failure (HF) and 17 patients without HF. The cardiac event rate was highest in the lowest SEMA3C tertile group in patients with HF. SEMA3C protects cardiomyocytes from cardiac hypertrophy, indicating that it could be a novel therapeutic target for CRS.
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| Free Research Field |
Cardiology
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| Academic Significance and Societal Importance of the Research Achievements |
心不全は本邦における重要な死因である。特に予後が悪いのが心腎症候群であるが、機序が解明されておらず、確立した治療法がないのが現状である。今回、我々は腎尿細管から分泌されるSemaphorin3Cが低下すると、心腎症候群において病的心肥大や生存率が悪化することをin vivoの実験系で示した。In vitroの実験系では、Semaphorin 3Cのリコンビナント蛋白質を投与することで心筋細胞肥大を抑制する知見を得た。今後、Semaphorin 3Cによる薬物介入や遺伝子導入により心肥大や予後が改善するか追加検証を行い、新たな治療薬の開発を目指していきたい。
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