2. Academic Validation
  3. Hepatocyte mitochondrial DNA activated store-operated Ca2+ entry via Stim1/Orai1-induced podocyte injury in trichloroethylene sensitized mice: A new insight in liver and kidney crosstalk

Hepatocyte mitochondrial DNA activated store-operated Ca2+ entry via Stim1/Orai1-induced podocyte injury in trichloroethylene sensitized mice: A new insight in liver and kidney crosstalk

  • Toxicol Appl Pharmacol. 2025 Oct:503:117465. doi: 10.1016/j.taap.2025.117465.
Luo-Lun Dong 1,  Xue-Qian Jia 1,  Hai-Bo Xie 2,  Li-Fu Zhu 1,  Peng-Cheng Zhou 1,  Rui-Xuan Cheng 3,  Chun-Lin Cao 1,  Qi-Xing Zhu 4,  Jia-Xiang Zhang 5
Affiliations

Affiliations

  • 1 Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
  • 2 Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 3 Department of Dermatology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 4 Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. Electronic address: zqxing@yeah.net.
  • 5 Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. Electronic address: jiaxiang5337@ahmu.edu.cn.
PMID: 40669774 DOI: 10.1016/j.taap.2025.117465
Abstract

Previous clinical case studies revealed that patients with severe liver damage often develop kidney damage in occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). However, the mechanism of this crosstalk is unknown. In this study, we extracted hepatocyte mtDNA from TCE-sensitized positive mice and co-treated it with a mouse podocyte line, MPC5. The expression of the stromal interaction molecule 1 (Stim1) and calcium release-activated Calcium Channel protein 1 (Orai1) proteins did not change significantly with or without interference with the Stimulator of interferon gene (STING) protein in hepatocyte mtDNA pretreated MPC5 cells. Subsequently, siRNA interference treatment of Stim1 and Orai1, respectively, was found to significantly ameliorate the damage to podocytes. Moreover, lentiviral transfection for overexpression of the key protein Orai1 was carried out, and the expression of inflammatory factors was significantly elevated. In animal experiments, the SOCE inhibitor YM-58483 was used to treat TCE-sensitized mice, and the administration of YM-58483 alleviated the reduction in the expression of podocyte injury proteins. In summary, this study explored the role of hepatocyte mtDNA-mediated podocyte injury in CA2+ signaling pathway activation and immune kidney injury in TCE sensitization-positive mice. We found that hepatocyte mtDNA enhances SOCE by increasing the interaction between Orai1 and Stim1 and that SOCE activation mediated by hepatocyte mtDNA processing regulates the secretion of inflammatory factors by podocytes. SOCE inhibitors reversed this phenomenon and mitigated immune kidney damage caused by TCE sensitization. This study provides new insight into the mechanisms of renal damage in liver and kidney crosstalk induced by TCE sensitization.

Keywords

Crosstalk; Kidney; Liver; Mitochondrial DNA; Trichloroethylene.

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