Abstract P017: Contribution of High Mobility Group Box 1 to Hyperhomocysteinemia-induced Podocyte Injury and Glomerular Sclerosis
High mobility group box 1 protein (HMGB1), a nuclear DNA binding protein is released under pathological conditions and locally act as one of potent damage-associated molecular patterns (DAMPs) to produce tissue injury and chronic inflammation. However, it remains unknown so far whether HMGB1 is implicated in homocysteine (Hcys)-induced podocyte injury and glomerular sclerosis during hyperhomocysteinemia (hHcys). In the present study, we found that homocysteine (Hcys) dose-dependently increased the production of HMGB1 in cultured podocytes, and that HMGB1 binder and inhibitor, glycyrrhizin (Gly) completely blocked its release induced by Hcys. Furthermore, inhibition of HMGB1 preserved podocyte function by restoring Hcys-induced suppression of VEGF secretion, decrease in expression of podocin and elevation of desmin level (podocyte damage markers). In in vivo studies, C57BL/6J wild type mice were fed a folate free (FF) diet or normal chow for 8 weeks to produce hHcys and administrated with vehicle or glycyrrhizin (1mg/kg/day) locally into the renal cortex. Western blot analysis of renal tissue showed that the FF diet significantly increased HMGB-1 (2 folds) and desmin expression (1.8 folds) compared to control mice, which was blocked by HMGB 1 inhibitor Glycyrrhizin. The urinary protein and albumin excretion were significantly higher in mice on the FF diet compared to ND fed mice. In glycerrhizin treated mice, however, the hHcys-induced albuminuria was significantly lowered (urinary albumin excretion in vehicle- and glycerrhizin-treated hHcys was 50 ± 3 and 32 ± 2.5 μg/24h/g BW, respectively). Morphological examinations showed that hHcys-induced more profound injury in glomeruli of vehicle treated mice than in glycerrhizin treated mice (the glomerular damage index in vehicle and glycerrhizin-treated hHcys mice was: 2.8 ± 0.4 vs. 1.3 ± 0.3). Based on these results, it is concluded that HMGB1 is one of important mediators of hHcys-induced podocyte injury and glomerular sclerosis. HMGB1 may be a therapeutic target for treatment or prevention of glomerulosclerosis associated with hHcys.
Author Disclosures: K.M. Boini: None. M. Xia: None. S.M. Conley: None. G. Li: None. S. Koka: None. T.W. Gehr: None. P. Li: None.
- © 2015 by American Heart Association, Inc.