Nephrocystin-4 exacerebates cardiac function in pressure overload

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08464
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamagata University
• Principal Investigator: Takahashi Hiroki 山形大学, 医学部, 講師 (90400548)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: Nephrocystin-4 / Pressure overload / Hippo pathway / Insulin signaling / ITCH

Outline of Final Research Achievements

We have reported that Nephrocystin-4 (NPHP4), a major cause of nephrocystin,was associated with the cardiovascular mortality in general population. It remains undetermined the functional role of NPHP4 in the development of cardiac disease. We generated NPHP4 knockout mice using CRISPER-Cas9. Thoracic transverse aortic constriction (TAC) was performed in NPHP4 knockout mice and wild-type littermates. RNA-sequencing of heart tissue revealed the mitochondrial proteins were down-regulated in NPHP4 KO mice. NPHP4 KO mice showed exacerbated cardiac function and had a lower survival rate than wild-type littermates. Immunoprecipitation demonstrated that NPHP4 interacted with ubiquitin E3 ligase ITCH in cardiomyocytes. Knockdown study of NPHP4 using siRNA showed an activation of Hippo pathway. Insulin signaling was inhibited in response to IGF-1 stimulation in cardiomyocytes after NPHP4 knockdown. Deficiency of NPHP4 may be the genetic risk for cardiac disease.

Free Research Field

Cardiology

Academic Significance and Societal Importance of the Research Achievements

心疾患の発症には、遺伝的危険因子が関与する。我々は、本邦一般住民においてNPHP4遺伝子多型が心血管死の危険因子であることを報告した。また、本研究では、大動脈縮窄術による圧負荷に対して、野生型に比べてNPHP4ノックアウトマウスはミトコンドリア機能が悪化し、心機能や予後が悪化することを示した。更に、NPHP4はユビキチン転移酵素ITCHと相互作用し、Hippo経路やInsulin経路を調節することを示した。以上の知見を踏まえ、NPHP4の遺伝子検査が将来の心疾患発症予測につながる可能性が示唆された。今後、NPHP4に対して治療介入することで心疾患発症を予防できるか追加検討が必要である。