Glomerular Damage in Trichloroethylene-Sensitized Mice: Targeting Cathepsin L-Induced Hyperactive mTOR Signaling

Feng Wang; Yuying Dai; Meng Huang; Chenchen Zhang; Liping Huang; Hui Wang; Liangping Ye; Qifeng Wu; Xuejun Zhang; Qixing Zhu

doi:10.3389/fphar.2021.639878

Glomerular Damage in Trichloroethylene-Sensitized Mice: Targeting Cathepsin L-Induced Hyperactive mTOR Signaling

Front Pharmacol. 2021 Jul 29:12:639878. doi: 10.3389/fphar.2021.639878. eCollection 2021.

Authors

Feng Wang^{1

2}, Yuying Dai³, Meng Huang³, Chenchen Zhang¹, Liping Huang³, Hui Wang^{2

4}, Liangping Ye^{2

4}, Qifeng Wu⁵, Xuejun Zhang^{2

4}, Qixing Zhu^{2

4}

Affiliations

¹ Department of Dermatology, The Second Hospital of Anhui Medical University, Hefei, China.
² Key Laboratory of Dermatology, Ministry of Education, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
³ Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China.
⁴ Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁵ Poison Control Center, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China.

Abstract

Trichloroethylene (TCE) is a serious health hazard for workers with daily exposure, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and glomerular damage. Recent studies suggest that mTORC1 signaling is activated in various glomerular disorders; however, the role of mTORC1 signaling in TCE-induced glomerular damage remains to be explored. In the present study, 6 OMDT patients were enrolled and a TCE-sensitized mouse model was established to investigate molecular mechanisms underlying the glomerular damage associated with OMDT. Glomerular damage was assessed by levels of urine nephrin, H&E staining, and renal function test. Ultrastructural change of podocyte was investigated by transmission electron microscopy. The podocyte-related molecules including nephrin, α-actinin-4, and integrin β1 were visualized by immunofluorescence. The activation of mTORC1 signaling was confirmed by Western blot. Glomerular apoptosis was examined by the TUNEL test and Western blotting. Expression and location of cathepsin L (CTSL) were assessed by RT-PCR and immunofluorescence. Our results showed that TCE sensitization caused damage to glomerular structural integrity and also increased the activation of mTORC1 signaling, which was accompanied by podocyte loss, hypertrophy, and glomerular apoptosis. Importantly, we also found that over-expressed CTSL was mainly located in podocyte and CTSL inhibition could partially block the activation of mTORC1 signaling. Thus, our findings suggested a novel mechanism whereby hyperactive mTOR signaling contributes to TCE sensitization-induced and immune-mediated glomerular damage via CTSL activation.

Keywords: apoptosis; cathepsin L; mTOR; podocyte; trichloroethylene.