Department of Nephrology, Zhongshan Hospital, Fudan University, China; Shanghai Medical Center for Kidney, China; Shanghai Key Laboratory of Kidney and Blood Purifcation, China.
Department of Nephrology, Zhongshan Hospital, Fudan University, China; Shanghai Medical Center for Kidney, China; Shanghai Key Laboratory of Kidney and Blood Purifcation, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China.
Life Sci. 2020 Dec 15;263:118672. doi: 10.1016/j.lfs.2020.118672. Epub 2020 Oct 26.
Cisplatin is an anticancer agent marred by nephrotoxicity. Limiting this adverse effect may allow the use of higher doses to improve its efficacy. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis and repair of renal diseases. BIO, a small molecule agonist of this pathway, exerted a protective effect in adriamycin nephropathy and promoted nephrogenesis. The aim of this study, therefore, was to investigate whether Wnt/β-catenin agonist BIO could protect against cisplatin-induced nephrotoxicity in vivo and in vitro, as well as its possible mechanism.
Male mice and human renal proximal tubular cells (HK-2) were subjected to cisplatin to study reno-protective effect of BIO. Renal function, cell viability, tubular apoptosis, production of reactive oxygen species (ROS) and proliferative level were analyzed respectively. Additionally, xenograft model was induced to investigate if BIO would impair the antitumor effect of cisplatin.
Cisplatin increased serum creatinine levels and promoted histological renal injury as well as oxidative stress levels. Besides, renal apoptotic level and the expression of pro-apoptotic proteins, Bax/bcl-2 and cleaved-caspase3 included, in the kidney were increased. All these features were decreased by BIO, which also activated Wnt/β-catenin pathway in cisplatin-induced nephrotoxicity. Similarly, accompanied by the motivation of Wnt/β-catenin pathway, BIO exerted a positively protective effect on HK-2 challenged cisplatin. Last, the chemotherapeutic effects of cisplatin in xenograft mice of ovary tumor models and in lung cancer cells weren't compromised by BIO.
Wnt/β-catenin agonist BIO has the potential to prevent cisplatin nephrotoxicity without compromising its anti-proliferation efficacy.
顺铂是一种具有肾毒性的抗癌药物。限制这种不良反应可能允许使用更高剂量以提高其疗效。Wnt/β-连环蛋白信号通路在肾发生和肾脏疾病的修复中起着关键作用。该途径的小分子激动剂 BIO 在阿霉素肾病中发挥了保护作用，并促进了肾发生。因此，本研究旨在探讨 Wnt/β-连环蛋白激动剂 BIO 是否可以在体内和体外预防顺铂引起的肾毒性，以及其可能的机制。
雄性小鼠和人肾近端管状细胞（HK-2）用顺铂处理，以研究 BIO 的肾保护作用。分别分析肾功能、细胞活力、管状细胞凋亡、活性氧（ROS）产生和增殖水平。此外，还诱导异种移植模型以研究 BIO 是否会损害顺铂的抗肿瘤作用。
顺铂增加血清肌酐水平，并促进组织学肾损伤和氧化应激水平。此外，肾凋亡水平以及肾组织中促凋亡蛋白 Bax/bcl-2 和 cleaved-caspase3 的表达增加。这些特征都被 BIO 降低，同时 BIO 还激活了顺铂诱导的肾毒性中的 Wnt/β-连环蛋白通路。同样，伴随着 Wnt/β-连环蛋白通路的激活，BIO 对顺铂攻击的 HK-2 发挥了积极的保护作用。最后，BIO 并未损害顺铂在卵巢肿瘤模型异种移植小鼠和肺癌细胞中的化疗效果。
Wnt/β-连环蛋白激动剂 BIO 具有预防顺铂肾毒性而不损害其抗增殖作用的潜力。
