内质网
未折叠蛋白反应
细胞生物学
细胞凋亡
信号转导
车站3
磷酸化
化学
激酶
下调和上调
生物
生物化学
基因
作者
Xin Chou,Kunpeng Ma,Yue Shen,Zhen Min Ma,Qing Wu,Daoyuan Sun
出处
期刊:Toxicology
[Elsevier]
日期:2021-04-01
卷期号:456: 152769-152769
被引量:3
标识
DOI:10.1016/j.tox.2021.152769
摘要
Cadmium (Cd) is a nephrotoxicant that primarily damages renal proximal tubular cells. Endoplasmic reticulum (ER) stress is mechanistically linked to Cd-induced renal injury. Inositol-requiring enzyme 1 (IRE-1α) is the most conserved ER stress transducer protein, which has both kinase and endonuclease activities. This study aimed to investigate whether the two enzymatic activities of IRE-1α have different effects in its regulation of Cd-induced apoptosis. Human proximal tubular (HK-2) cells were treated with 20 μM CdCl 2 for 0−24 h, and mice were fed with Cd-containing drinking water (100−400 mg/L) for 24 weeks. We found that Cd increased cell apoptosis in HK-2 cells and mouse kidneys in a time-dependent manner. Such cytotoxicity was correlated with activation of ER stress, evidenced by upregulation of IRE-1α and its target protein spliced X-box binding protein-1 (XBP-1 s). Interestingly, inhibition of IRE-1α kinase activity by KIRA6 was more protective against Cd-induced apoptosis than inhibition of its RNase activity by STF-083010. Mechanistically, Cd promoted the binding of IRE-1α with signal transducer and activator of transcription-3 (STAT3) leading to elevated phosphorylation of STAT3 at Ser727 and thus inactivation of STAT3 signaling, which resulted in aggravation of Cd-induced apoptosis in HK-2 cells. Collectively, our findings indicate that IRE-1α coordinate ER stress and STAT3 signaling in mediating Cd-induced renal toxicity, suggesting that targeting IRE-1α might be a potential therapeutic approach for Cd-induced renal dysfunction and disease.
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