Dual role of inositol-requiring enzyme 1α (IRE-1α) in Cd-induced apoptosis in human renal tubular epithelial cells: Endoplasmic reticulum stress and STAT3 signaling activation.

Autor: Chou X; Shanghai Pulmonary Hospital Affiliated Tongji University, 507 Zhengmin Road, Shanghai, 200433, China; School of Public Health, Fudan University, 130 Dong'An Road, Shanghai, 200032, China., Ma K; Shanghai Pulmonary Hospital Affiliated Tongji University, 507 Zhengmin Road, Shanghai, 200433, China., Shen Y; Shanghai Pulmonary Hospital Affiliated Tongji University, 507 Zhengmin Road, Shanghai, 200433, China., Min Z; Shanghai Pulmonary Hospital Affiliated Tongji University, 507 Zhengmin Road, Shanghai, 200433, China., Wu Q; School of Public Health, Fudan University, 130 Dong'An Road, Shanghai, 200032, China. Electronic address: qingwu@fudan.edu.cn., Sun D; Shanghai Pulmonary Hospital Affiliated Tongji University, 507 Zhengmin Road, Shanghai, 200433, China. Electronic address: daoyun_sun@163.com.
Jazyk: angličtina
Zdroj: Toxicology [Toxicology] 2021 May 30; Vol. 456, pp. 152769. Date of Electronic Publication: 2021 Apr 01.
DOI: 10.1016/j.tox.2021.152769
Abstrakt: 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.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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