Blockade of Indoleamine 2,3-Dioxygenase attenuates lipopolysaccharide-induced kidney injury by inhibiting TLR4/NF-κB signaling

Abstract

Blockade of indoleamine 2,3-dioxygenase (IDO) has been shown to alleviate lipopolysaccharide (LPS)-induced endotoxic shock and reduce sepsis mortality, but its effect on LPS-induced kidney damage has not been reported. Herein, we established a mouse kidney injury model by intraperitoneal injection of 10 mg/kg LPS and established an in vitro renal tubular epithelial cell injury model by stimulating TCMK-1 cells with 10 mg/L LPS. We found that pretreatment with 1-methyl tryptophan (1-MT), an IDO inhibitor, significantly improved LPS-induced mouse survival, and IDO knockout (KO) mice also had higher survival rates after LPS exposure than wild-type mice. At the same time, IDO KO or pretreatment with 1-MT not only reduced serum creatinine, blood urea nitrogen, renal tubular injury pathological score, but also inflammatory factors and oxidative stress status in serum or kidney of LPS-exposed mice. In vitro, blockade of IDO with 1-MT significantly inhibited LPS-induced apoptosis, inflammation and oxidative stress in TCMK-1 cells. In addition, blockade of IDO significantly inhibited LPS-activated TLR4/NF-κB signaling pathway in kidney of mice or in TCMK-1 cells. In conclusion, our results suggested that blockade of IDO attenuated kidney inflammation, apoptosis and oxidative stress to protect against LPS-induced septic kidney injury via inhibiting the TLR4/NF-κB signaling pathway.

Keywords: Indoleamine 2,3-dioxygenase; Kidney injury; Lipopolysaccharide; TLR4/NF-κB.