Tim-3 protects against cisplatin nephrotoxicity by inhibiting NF-κB-mediated inflammation

Abstract

The impact of Tim-3 (T cell immunoglobulin and mucin domain-containing protein 3) on cisplatin-induced acute kidney injury was investigated in this study. Cisplatin-induced Tim-3 expression in mice kidney tissues and proximal tubule-derived BUMPT cells in a time-dependent manner. Compared with wild-type mice, Tim-3 knockout mice have higher levels of serum creatinine and urea nitrogen, enhanced TUNEL staining signals, more severe 8-OHdG (8-hydroxy-2’ -deoxyguanosine) accumulation, and increased cleavage of caspase 3. The purified soluble Tim-3 (sTim-3) protein was used to intervene in cisplatin-stimulated BUMPT cells by competitively binding to the Tim-3 ligand. sTim-3 obviously increased the cisplatin-induced cell apoptosis. Under cisplatin treatment conditions, Tim-3 knockout or sTim-3 promoted the expression of TNF-α (tumor necrosis factor-alpha) and IL-1β (Interleukin-1 beta) and inhibited the expression of IL-10 (interleukin-10). NF-κB (nuclear factor kappa light chain enhancer of activated B cells) P65 inhibitor PDTC or TPCA1 lowed the increased levels of creatinine and BUN (blood urea nitrogen) in cisplatin-treated Tim-3 knockout mice serum and the increased cleavage of caspase 3 in sTim-3 and cisplatin-treated BUMPT cells. Moreover, sTim-3 enhanced mitochondrial oxidative stress in cisplatin-induced BUMPT cells, which can be mitigated by PDTC. These data indicate that Tim-3 may protect against renal injury by inhibiting NF-κB-mediated inflammation and oxidative stress.

Time-restricted feeding protects against cisplatin-induced acute kidney injury in mice

“…3B). NF-κB is an important nuclear transcript factor that induces the expression of various pro-inflammatory cytokines [17]. Therefore, we investigated NF-κB expression during inflammation in cisplatin-induced AKI.…”

The cross-talk between macrophages and tumor cells as a target for cancer treatment

“…TIMs are phosphatidylserine receptors mainly expressed on antigen−presenting cells that are involved in the recognition and efferocytosis of apoptotic cells. They are expressed in immune cells such as NK, T, B, and mast cells and participate in multiple aspects of immune regulation but are also abnormally expressed in cancer cells, contributing to immunosuppression ( 64 , 179 , 180 ). Studies demonstrated that blockade of TIMs improved the anticancer effectiveness of T-cell responses in cancer patients and enhanced the immune cells’ stimulatory properties ( 64 , 180 ).…”