Activation of the <i>N</i>‐methyl‐<scp>d</scp>‐aspartate receptor is involved in glyphosate‐induced renal proximal tubule cell apoptosis

Journal of Applied Toxicology - Tập 39 Số 8 - Trang 1096-1107 - 2019
Hui Gao1, Jing Chen2, Fan Ding1, Xin Chou1, Xiaoyan Zhang2,3,4, Yi Wan5, Jianying Hu5, Qing Wu1
1School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
2Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
3Shanghai Institute of Kidney and Dialysis, Shanghai 200032, China
4Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai 200032, China
5Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China

Tóm tắt

AbstractGlyphosate‐based herbicides have been used worldwide for decades and have been suggested to induce nephrotoxicity, but the underlying mechanism is not yet clear. In this study, we treated a human renal proximal tubule cell line (HK‐2) with glyphosate for 24 hours at concentrations of 0, 20, 40 and 60 μm. Glyphosate was found to reduce cell viability and induce apoptosis and oxidative stress in a dose‐dependent manner. Because the chemical structures of glyphosate and those of its metabolite AMPA are similar to glycine and glutamate, which are agonists of the N‐methyl‐d‐aspartate receptor (NMDAR), we investigated the potential role of the NMDAR pathway in mediating the proapoptotic effect of glyphosate on proximal tubule cells. We found that NMDAR1 expression, as well as intracellular Ca2+ ([Ca2+]i) and reactive oxygen species (ROS) levels, increased after glyphosate treatment. Blocking NMDAR attenuated glyphosate‐induced upregulation of [Ca2+]i and ROS levels as well as apoptosis. Meanwhile, inhibition of [Ca2+]i reduced glyphosate‐induced ROS and apoptosis, and inhibition of ROS alleviated glyphosate‐induced apoptosis. In mice exposed to 400 mg/kg glyphosate, the urine low molecular weight protein levels started to increase from day 7. Upregulation of apoptosis and NMDAR1 expression in renal proximal tubule epithelium and an imbalance of oxidant and antioxidative products were observed. These results strongly suggest that activation of the NMDAR1 pathway, together with its downstream [Ca2+]i and oxidative stress, is involved in glyphosate‐induced renal proximal tubule epithelium apoptosis.

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Thông tin xuất bản

Journal of Applied Toxicology

Tập 39 Số 8

1096-1107

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