TRIM47 promotes trichloroethylene-induced immune kidney injury by degrading SIRT1 through ubiquitination.

Trichloroethylene (TCE) exposure can cause occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) and is often linked to kidney damage. Previous study showed that sirtuin 1 (SIRT1) expression in kidney cells is reduced and associated with podocyte injury, but the exact mechanism is unclear. This study used TCE-sensitized mouse model and in vitro studies to investigate how SIRT1 affects endothelial cells and podocytes communication. Results showed that the administration of tumor necrosis factor α (TNFα) inhibitor R7050 in mice reduced tripartite motif 47 (TRIM47) expression, restored SIRT1 levels, and lessened kidney damage. Further TRIM47 knockdown inhibited its binding to SIRT1, reduced SIRT1 ubiquitination, inhibited acetylated high mobility group box 1 (AcHMGB1) expression, and alleviated podocyte damage. In vitro experiments demonstrated a significant increase in the expression level of AcHMGB1 in cell supernatant and elevated human renal podocyte cell lines (HPCs) apoptosis level within the TNF-α-treated human glomerular vascular endothelial cell lines (HRGECs) and HPCs co-culture system. Additionally, HRGECs were treated with the proteasome inhibitor MG132 to inhibit proteasome activity, thereby inhibiting the degradation of proteins via the ubiquitin-proteasome pathway, and found that MG132 effectively inhibited the degradation of SIRT1. In conclusion, TNFα enhanced the expression of TRIM47 in renal vascular endothelial cells of TCE-sensitized mice. Subsequently, TRIM47 interacted with SIRT1, facilitating its ubiquitination and subsequent degradation, thereby inhibited the deacetylation of HMGB1. This process resulted in the translocation of substantial quantities of AcHMGB1 from the cytoplasm to extracellular milieu, where it interacts with podocytes and induces apoptosis.