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.
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.
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DOI：
10.1016/j.cellsig.2023.110878
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发表时间：
2023-08
影响因子：
4.8
通讯作者：
Zhaoxing Sun;Yi-chun Ning;Huan Wu;Shulan Guo;Xiaoyan Jiao;Ji Ji-Ji;Xiaoqiang Ding;Xiaofang Yu
中科院分区：
文献类型：
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作者：
Zhaoxing Sun;Yi-chun Ning;Huan Wu;Shulan Guo;Xiaoyan Jiao;Ji Ji-Ji;Xiaoqiang Ding;Xiaofang Yu
顺铂是一种广泛用于治疗实体瘤的化疗药物;然而，其临床应用受到副作用，特别是肾毒性的限制。顺铂诱导的急性肾损伤（阿基）的特征是DNA损伤、细胞周期停滞和线粒体氧化应激。最近的研究表明，14-3-3 β在癌症、神经疾病和肾脏疾病中起着重要作用，尽管顺铂诱导的阿基的调控机制尚未完全阐明。在目前的研究中，我们发现当用顺铂处理时，14 -3-3 β mRNA在人肾类器官（GSE 145085）中上调;随后，这在实验小鼠中得到证实。在顺铂诱导的阿基中，14-3-3（BV 02）蛋白相互作用抑制剂的应用导致肾功能下降，沿着细胞凋亡、线粒体功能障碍和氧化应激。因此，在顺铂处理的NRK-52 E细胞中敲低14-3-3 β导致细胞凋亡、细胞周期停滞、活性氧（ROS）的产生和脂质代谢障碍增加。此外，在体内和体外阻断14-3-3 β-catenin可抑制β-catenin及其核转位，从而下调顺铂诱导的损伤中下游基因cyclin D1的表达。相反，14-3-3 β的过表达在体内和体外均减轻顺铂引起的损伤。此外，β-catenin的非特异性激动剂BIO通过激活β-catenin来逆转14-3-3 β敲低在NRK-52 E细胞中顺铂诱导的损伤方面的作用。接下来，我们通过CO-IP和免疫荧光验证了14 - 3-3 β和β-catenin之间的直接相互作用。总的来说，这些发现表明14-3-3 β通过促进β-连环蛋白的核转位改善线粒体功能和增殖与凋亡之间的平衡来保护免受顺铂诱导的阿基。
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 that14-3-3ζmRNA 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, bothin vivoandin vitro, suppressed β-catenin and its nuclear translocation, thus downregulating expression of the downstream genecyclin D1in cisplatin-induced damage. In contrast, the overexpression of 14-3-3ζ alleviated the injury caused by cisplatin bothin 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 - 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.