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Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells.
Toxicol Lett. 2019 Sep 01; 311:105-113.TL

Abstract

Excessive accumulation of cadmium (Cd) in retina plays an important role in tobacco smoking-associated age-related macular degeneration (AMD). Plenty of evidence has revealed that the retinal pigment epithelium (RPE) is the primary site of pathology in AMD. Our current study demonstrated that Cd induced apoptosis in a human RPE cell line ARPE-19 cells, as it dose-dependently caused cell viability loss and activated caspase-3. The reactive oxygen species (ROS) were confirmed to be important mediators for Cd-triggered cell death in ARPE-19 cells. We found that endoplasmic reticulum (ER) stress was activated as its marker BiP was remarkably upregulated by Cd-exposure. Whereas the antioxidants N-acetylcysteine (NAC) and Tempol significantly suppressed the expression of BiP and CHOP, suggesting that ROS generation is an early trigger of Cd-activated ER stress. Furthermore, we found that Cd-induced oxidative stress significantly increased autophagic flux and p62 expression. A temporal impact of Cd exposure is possibly existed in p62 expression in ARPE-19 cells. Moreover, an ER stress inhibitor salubrinal diminished Cd-induced LC3BII expression and attenuated cytotoxicity, indicating that ER stress mediates autophagy and was implicated in apoptosis of Cd-exposed ARPE-19 cells. However, CHOP expression may not exert impact on the regulation of Cd-caused autophagy. Additionally, inhibition of autophagy with si-Beclin 1 and 3-Methyladenine significantly ameliorated Cd-induced CHOP expression and cytotoxicity, indicating that autophagy was detrimental in Cd-accumulated ARPE-19 cells, and a positive feedback regulation mechanism may exist between Cd-triggered ER stress and autophagy. Taken together, these results suggest that Cd-caused ER stress and autophagy are implicated in RPE cell death associated retinopathies especially related to smoking.

Authors+Show Affiliations

Central Laboratory, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.Central Laboratory, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.Central Laboratory, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.Central Laboratory, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China. Electronic address: liyijie12580@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31054874

Citation

Zhang, Lingmin, et al. "Endoplasmic Reticulum Stress and Autophagy Contribute to Cadmium-induced Cytotoxicity in Retinal Pigment Epithelial Cells." Toxicology Letters, vol. 311, 2019, pp. 105-113.
Zhang L, Xia Q, Zhou Y, et al. Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells. Toxicol Lett. 2019;311:105-113.
Zhang, L., Xia, Q., Zhou, Y., & Li, J. (2019). Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells. Toxicology Letters, 311, 105-113. https://doi.org/10.1016/j.toxlet.2019.05.001
Zhang L, et al. Endoplasmic Reticulum Stress and Autophagy Contribute to Cadmium-induced Cytotoxicity in Retinal Pigment Epithelial Cells. Toxicol Lett. 2019 Sep 1;311:105-113. PubMed PMID: 31054874.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells. AU - Zhang,Lingmin, AU - Xia,Qingqing, AU - Zhou,Yingying, AU - Li,Jie, Y1 - 2019/05/02/ PY - 2018/07/05/received PY - 2019/04/28/revised PY - 2019/05/01/accepted PY - 2019/5/6/pubmed PY - 2019/6/14/medline PY - 2019/5/6/entrez KW - Autophagy KW - Cadmium KW - ER-stress KW - Reactive oxygen species KW - Retinal pigment epithelial cell SP - 105 EP - 113 JF - Toxicology letters JO - Toxicol. Lett. VL - 311 N2 - Excessive accumulation of cadmium (Cd) in retina plays an important role in tobacco smoking-associated age-related macular degeneration (AMD). Plenty of evidence has revealed that the retinal pigment epithelium (RPE) is the primary site of pathology in AMD. Our current study demonstrated that Cd induced apoptosis in a human RPE cell line ARPE-19 cells, as it dose-dependently caused cell viability loss and activated caspase-3. The reactive oxygen species (ROS) were confirmed to be important mediators for Cd-triggered cell death in ARPE-19 cells. We found that endoplasmic reticulum (ER) stress was activated as its marker BiP was remarkably upregulated by Cd-exposure. Whereas the antioxidants N-acetylcysteine (NAC) and Tempol significantly suppressed the expression of BiP and CHOP, suggesting that ROS generation is an early trigger of Cd-activated ER stress. Furthermore, we found that Cd-induced oxidative stress significantly increased autophagic flux and p62 expression. A temporal impact of Cd exposure is possibly existed in p62 expression in ARPE-19 cells. Moreover, an ER stress inhibitor salubrinal diminished Cd-induced LC3BII expression and attenuated cytotoxicity, indicating that ER stress mediates autophagy and was implicated in apoptosis of Cd-exposed ARPE-19 cells. However, CHOP expression may not exert impact on the regulation of Cd-caused autophagy. Additionally, inhibition of autophagy with si-Beclin 1 and 3-Methyladenine significantly ameliorated Cd-induced CHOP expression and cytotoxicity, indicating that autophagy was detrimental in Cd-accumulated ARPE-19 cells, and a positive feedback regulation mechanism may exist between Cd-triggered ER stress and autophagy. Taken together, these results suggest that Cd-caused ER stress and autophagy are implicated in RPE cell death associated retinopathies especially related to smoking. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/31054874/Endoplasmic_reticulum_stress_and_autophagy_contribute_to_cadmium_induced_cytotoxicity_in_retinal_pigment_epithelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(19)30134-1 DB - PRIME DP - Unbound Medicine ER -