14-3-3ζ targets β-catenin nuclear translocation to maintain mitochondrial homeostasis and promote the balance between proliferation and apoptosis in cisplatin-induced acute kidney injury

Cisplatin is a chemotherapeutic agent that is used extensively to treat solid tumors; however, its clinical application is limited by side effects, especially nephrotoxicity. Cisplatin-induced acute kidney injury (AKI) is characterized by DNA damage, cell-cycle arrest, and mitochondrial oxidative stress. Recent research demonstrated that 14-3-3ζ plays an important role in cancers, nerve disease, and kidney disease, although the regulatory mechanisms underlying cisplatin-induced AKI have yet to be fully elucidated. In the present study, we found that 14-3-3ζ mRNA was upregulated in human kidney organoids (GSE145085) when treated with cisplatin; subsequently, this was confirmed in experimental mice. The application of a protein interaction inhibitor for 14-3-3 (BV02) resulted in a decline in renal function, along with Apoptosis, mitochondrial dysfunction, and oxidative stress in cisplatin-induced AKI. Accordingly, the knockdown of 14-3-3ζ in cisplatin-treated NRK-52E cells led to increased Apoptosis, cell-cycle arrest, the production of Reactive Oxygen Species (ROS), and lipid dysbolism. Furthermore, the blockade of 14-3-3ζ, both in vivo and in vitro, suppressed β-catenin and its nuclear translocation, thus downregulating expression of the downstream gene cyclin D1 in cisplatin-induced damage. In contrast, the overexpression of 14-3-3ζ alleviated the injury caused by cisplatin both in vivo and in vitro. Furthermore, a non-specific agonist of β-catenin, BIO, reversed the effects of 14-3-3ζ knockdown in terms of cisplatin-induced damage in NRK-52E cells by activating β-catenin. Next, we verified the direct interaction between 14 and 3-3ζ and β-catenin by CO-IP and immunofluorescence. Collectively, these findings indicate that 14-3-3ζ protects against cisplatin-induced AKI by improving mitochondrial function and the balance between proliferation and Apoptosis by facilitating the nuclear translocation of β-catenin.

Acute kidney injury; Apoptosis; Cell cycle; Cisplatin; Mitochondrial homeostasis; ROS.