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Abstract: SA-PO155

14-3-3ζ Targets β-Catenin Nuclear Translocation to Maintain Mitochondrial Homeostasis, Promoting Balance of Proliferation and Apoptosis in Cisplatin-Induced AKI

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sun, Zhaoxing, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China
  • Ding, Xiaoqiang, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China
  • Yu, Xiaofang, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China
Background

Cisplatin, an extensively used chemotherapeutic agent for solid tumors, is limited in clinical use due to its side effects, especially nephrotoxicity. Cisplatin-induced acute kidney injury (AKI) is characterized by DNA damage, cell cycle arrest and mitochondrial oxidative stress. Recent work demonstrated that 14-3-3ζ plays important role in cancers, nerve disease and kidney disease, but the role and regulatory mechanism in cisplatin AKI remain to be further clarified.

Methods

Here, we found that 14-3-3ζ mRNA was upregulated in human kidney organoids (GSE145085) when treated with cisplatin, which was confirmed in experimental mice. Then, we used inhibitor for 14-3-3 (BV02) in animal experiment, knocking down and overexpressing 14-3-3ζ respectively in vitro experiments to test the role of 14-3-3ζ in cisplatin-induced AKI.

Results

The use of protein interaction inhibitor for 14-3-3 (BV02) aggregated drop of renal function, apoptosis, mitochondrial dysfunction and oxidative stress in cisplatin-induced AKI. Accordingly, increased apoptosis, cell cycle arrest, ROS production and lipid dysbolism in cisplatin-treated NRK-52E cells were exacerbated in cells knocking down 14-3-3ζ. Besides, blocking 14-3-3ζ both in vivo and in vitro suppressed β-catenin and its nuclear translocation, downregulating the expression of downstream gene cyclin D1 in cisplatin-induced damage. In contrast, overexpression of 14-3-3ζ relieved injury caused by cisplatin and promoted nuclear transportation of β-catenin. Further, a non-specific agonist of β-catenin BIO reversed the effects of knocking down 14-3-3ζ in cisplatin-induced damage in NRK-52E by activating β-catenin. The direct interaction between 14-3-3ζ and β-catenin was then verified.

Conclusion

Taken together, these findings indicate that 14-3-3ζ protects against cisplatin-induced AKI by improving mitochondrial function and balance of proliferation and apoptosis through facilitating β-catenin nuclear translocation.

Funding

  • Government Support – Non-U.S.