Renal tubular cell necroptosis: A novel mechanism of kidney damage in trichloroethylene hypersensitivity syndrome mice

Abstract

Trichloroethylene (TCE) hypersensitivity syndrome (THS), called occupational medicamentosa-like dermatitis due to TCE (OMDT) in China, is a fatal occupational disorder caused by TCE exposure. Visceral damage, including kidney injury, is one of the major complications. Necroptosis is a regulated cell death form linked to local inflammatory response. This study aimed to investigate whether renal cell necroptosis was involved in TCE-induced kidney injury. A Balb/c mouse model of TCE sensitization was utilized to study mechanisms of modulation of TCE-induced renal necroptosis. Renal histology (using light and transmission electron microscopy) and renal tubular impairment indexes, including α1-microglobulin (α1-MG), and β2-microglobulin (β2-MG), were evaluated. In addition, tissue expression of necroptosis-related proteins, including tumor necrosis factor (TNF)-α, TNF receptor 1 (TNFR1), receptor-interacting protein kinase 3 (RIPK3), p-RIK3, mixed lineage kinase domain-like protein (MLKL), and p-MLKL, were also evaluated. The study here confirmed TCE sensitization caused damage to renal tubules and renal tubular epithelial cell (RTEC) necroptosis. In mice treated with R7050 (a specific TNFα antagonist), it was also seen that inhibition of TNFα expression could effectively inhibit RTEC necroptosis and improve renal function in the TCE-sensitized mice. Taken together, these results help to define a novel mechanism by which RTEC necroptosis plays a key role in TCE-induced kidney damage.

Keywords:

• Trichloroethylene hypersensitivity syndrome
• trichloroethylene
• renal tubular epithelial cell
• necroptosis
• tumor necrosis factor

Additional potential source for correspondence

Dr. Qixing Zhu, Department of Dermatology and Key Laboratory of Dermatology, Ministry of Education, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, China. (T) 8655162923009 (E) [email protected].

Disclosure statement

The authors declare no conflicts of interest. The authors alone are responsible for the content of this manuscript.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [No. 81874259], the Promotion Plan for Basic and Clinical Cooperative Research of Anhui Medical University [Grant No. 2020xkjT041], and the Incubation Plan for National Natural Science Foundation of the second hospital of Anhui Medical University [Grant No. 2020GMFY03].