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Abstract: FR-PO387

The Role and Mechanism of Ubiquitin-Specific Protease 25 in Cardiorenal Syndrome Type 4

Session Information

  • Hypertension and CVD: Basic
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1601 Hypertension and CVD: Basic

Authors

  • He, Fan, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Zhan, Xiaona, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Yang, Yi, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Li, Qing, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Xu, Gang, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
Background

The development of chronic kidney disease will lead to cardiorenal syndrome type 4 (CRS4). At present, there is no research on ubiquitin-specific protease 25 (USP25) in CRS4. The aim of this research was to investigate the function and mechanism of USP25 in CRS4.

Methods

C57BL/6 mice received 5/6 nephrectomy and were fed with high phosphate diet to establish the model of CRS4. The express levels of USP25 in the heart of mice in the CRS4 group and the H9C2 rat cardiomyoblast cell line treated with high phosphate (HP) was detected. The changes of hypertrophic markers and cross-sectional area of H9C2 cells in the siUSP25 + HP group were detected by qPCR and phalloidin staining. qPCR and echocardiography were used to compare the degree of cardiac hypertrophy in usp25+/+-CRS4 mice and usp25-/--CRS4 mice. To prove that USP25 regulated the cardiac hypertrophy in CRS4 through PTEN/AKT signaling pathway, the effect of knockout of USP25 in vivo or knockdown of USP25 in vitro on the AKT signaling pathway in cardiomyocytes was detected by western blot. The interaction between USP25 and PTEN was verified by immunoprecipitation, and the ubiquitination level and type of ubiquitination of PTEN in cells from the siNC group and siUSP25 group were detected. The degree of cardiomyocyte hypertrophy in the plasmid-USP25+HP+PTEN inhibitor group and plasmid-USP25+HP+DMSO was detected by qPCR and phalloidin staining.

Results

The level of USP25 in the heart of mice in the CRS4 group and the cells in the HP group were increased. In H9C2 cells stimulated by HP, knockdown of USP25 in vitro aggravated cardiomyocyte hypertrophy. In CRS4 mice, knockout of USP25 in vivo aggravated cardiac hypertrophy. Knockout of USP25 in vivo or knockdown of USP25 in vitro promoted the activation of the AKT signaling pathway in cardiomyocytes. The results of immunoprecipitation suggested that USP25 interacted with PTEN. The ubiquitination level of PTEN in the siUSP25 group was higher than that in the siNC group, and the increased ubiquitination type was K63-linked ubiquitination. In vitro, PTEN inhibitor could attenuate the anti-hypertrophic effect of overexpression of USP25 in H9C2 cells.

Conclusion

USP25 stabilized PTEN by removing the K63-linked ubiquitin chains of PTEN, which inhibited the activation of the AKT signaling pathway and relieved cardiac hypertrophy in CRS4.

Funding

  • Government Support – Non-U.S.