Department of Molecular Medical Biology, Kitasato University Graduate School of Medical Sciences, Kitasato 1-15-1, Minami-ku, Sagamihara-shi, Kanagawa, 252-0373, Japan.
Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
Mol Cell Biochem. 2022 Mar;477(3):689-699. doi: 10.1007/s11010-021-04295-y. Epub 2022 Jan 1.
Bardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2 pathway, is a potential therapeutic candidate for the treatment of kidney diseases. However, its effect against cellular senescence remains unclear. This study aimed to investigate whether CDDO-Me protects cells against cisplatin-induced cellular senescence using an in vitro model. The human renal proximal tubular epithelial cell line HK-2 was treated with cisplatin for 6 h, followed by treatment with or without CDDO-Me (0.1 or 0.2 μmol/L). Senescence markers were analyzed using western blotting and real-time PCR. Apoptosis was evaluated through TUNEL staining. Cisplatin induced changes in the levels of markers specific for proliferation, cell cycle, and senescence in a time- and dose-dependent manner. Furthermore, IL-6 and IL-8 levels in the culture medium increased markedly. These data suggested that cellular senescence-like alterations occurred in HK-2 cells exposed to cisplatin. CDDO-Me treatment reversed the cisplatin-mediated alterations in the levels of cellular senescence markers. The antioxidant enzymes, HO1, NQO1, GPX1, and CAT were upregulated by CDDO-Me treatment. Furthermore, CDDO-Me treatment induced apoptosis in cisplatin-exposed HK-2 cells. Pretreatment with Ac-DEVD-CHO, the caspase inhibitor, suppressed the reversal effect of CDDO-Me against cisplatin-induced cellular senescence-like alterations. This study showed that CDDO-Me attenuated cisplatin-induced premature senescence of HK-2 cells. This beneficial effect may be related to Nrf2 activation. Our findings also showed that CDDO-Me induced apoptosis in cisplatin-treated HK-2 cells, potentially protecting the kidneys from cellular senescence. CDDO-Me appears to be a candidate treatment for acute kidney injury.
Bardoxolone 甲基（甲基-2-氰基-3,12-二氧代齐墩果烷-1,9(11)二烯-28-酸酯（CDDO-Me）），一种核因子红细胞衍生 2 相关因子 2 通路的激活剂，是治疗肾脏疾病的潜在治疗候选药物。然而，其对细胞衰老的影响尚不清楚。本研究旨在通过体外模型研究 CDDO-Me 是否能保护细胞免受顺铂诱导的细胞衰老。用顺铂处理人肾近端肾小管上皮细胞系 HK-26 小时，然后用或不用 CDDO-Me（0.1 或 0.2μmol/L）处理。用 Western blot 和实时 PCR 分析衰老标志物。通过 TUNEL 染色评估细胞凋亡。顺铂以时间和剂量依赖的方式诱导增殖、细胞周期和衰老标志物的水平发生变化。此外，培养基中 IL-6 和 IL-8 的水平明显增加。这些数据表明，暴露于顺铂的 HK-2 细胞发生了类似衰老的改变。CDDO-Me 处理逆转了顺铂介导的细胞衰老标志物水平的改变。抗氧化酶 HO1、NQO1、GPX1 和 CAT 被 CDDO-Me 处理上调。此外，CDDO-Me 处理诱导暴露于顺铂的 HK-2 细胞凋亡。用 caspase 抑制剂 Ac-DEVD-CHO 预处理可抑制 CDDO-Me 对顺铂诱导的细胞衰老样改变的逆转作用。本研究表明，CDDO-Me 可减轻 HK-2 细胞顺铂诱导的过早衰老。这种有益作用可能与 Nrf2 激活有关。我们的研究结果还表明，CDDO-Me 诱导顺铂处理的 HK-2 细胞凋亡，可能保护肾脏免受细胞衰老。CDDO-Me 似乎是急性肾损伤的候选治疗药物。
