Role of High Mobility Group Box 1 in Trimethylamine‐N‐Oxide‐Induced Podocyte Injury and Glomerular Sclerosis

Abstract

The intestinal microbe derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of chronic kidney diseases (CKD). However, the molecular mechanisms of how TMAO induces CKD and progression of renal diseases are still unclear. Hence, the present study tested whether high mobility group box 1 (HMGB1) contributes to TMAO-induced podocyte injury and glomerular sclerosis. In in vitro, biochemical analysis showed that TMAO treatment significantly increased the HMGB1 expression compared to vehicle treated podocytes. However, prior treatment with glycyrrhizin, an HMGB1 binder abolished the TMAO-induced HMGB1 expression in podocytes. Furthermore, western blot and immunofluorescent analysis showed that significant decrease in the expression of the nephrin and podocin compared to control cells. However, prior treatment with glycyrrhizin attenuated the TMAO-induced nephrin and podocin reduction. In addition, TMAO treatment significantly increased the toll like receptor 4 (TLR4) expression and cell permeability compared to vehicle treated podocytes. However, prior treatment with glycyrrhizin attenuated the TMAO induced TLR4 expression and cell permeability. In in vivo studies, Western blot and biochemical analysis showed that TMAO treatment significantly increased the HMGB1, TLR4, desmin, urinary protein, urinary albumin, glomerular damage index and significantly decreased the podocin expression in TMAO treated mice compared to control mice. However, such TMAO-induced increase of HMGB1, TLR4, desmin expression, glomerular damage index, urinary protein, urinary albumin were attenuated in glycyrrhizin treated mice. Based on these results, it is concluded that HMGB1 is one of the important mediators of TMAO-induced podocyte injury and glomerular sclerosis.