Distinct roles of HMGB1 in the regulation of P‑glycoprotein expression in the liver and kidney of mice with lipopolysaccharide‑induced inflammation

Abstract

The role of high mobility group box 1 (HMGB1) in the regulation of efflux transporters in the liver and kidney remains unclear, although it has been reported that HMGB1 can increase P‑glycoprotein (P‑gp) expression in the brain. The present study aimed to clarify the involvement of HMGB1 in the regulation of P‑gp expression in the liver and kidney of mice with lipopolysaccharide (LPS)‑induced inflammation. Mice were treated with LPS or LPS + glycyrrhizin (GL); GL is as an HMGB1 inhibitor. Subsequently, the expression levels of transporters, such as P‑gp, and HMGB1 receptors, such as toll‑like receptor (TLR)4 and receptor for advanced glycation end‑products (RAGE), were determined by quantitative PCR and LC‑MS/MS‑based targeted proteomics. For the invitro study, HepG2 and KMRC‑1 cells were used, as was a co‑culture of KMRC‑1 and differentiated THP‑1 cells. The mRNA and protein expression levels of Mdr1a and Tlr4 in the kidneys of LPS + GL‑treated mice were significantly decreased compared with those in LPS mice. The results indicated that HMGB1 had little effect on the expression of Mdr1a and Tlr4 in the liver, since there was little change in of Mdr1a and Mdr1b expression between the LPS and LPS + GL‑treated mice. Notably, regarding MDR1 mRNA expression, KMRC‑1 cells were more responsive to LPS than HepG2 cells, and KMRC‑1 cells treated with LPS exhibited increased levels compared with control KMRC‑1 cells. In differentiated THP‑1 cells, LPS treatment decreased the mRNA expression levels of TLR4, whereas they were restored to control levels by HMGB1. In conclusion, HMGB1 in the plasma and TLR4 in macrophages may be involved in the regulation of P‑gp expression in the kidneys of inflamed mice.