Sirt1 and HMGB1 Regulate the AGE-Induced Pro-Inflammatory Cytokines in Human Retinal Cells.

BACKGROUND

Advanced glycation end products (AGEs) accumulate in the retinal vascular cells, neurons, and glias of patients with diabetes mellitus and lead to the pathogenesis of diabetic retinopathy (DR).

METHODS

In the present study, to elucidate the orchestrated interactions of high mobility group box 1 (HMGB1) and silent mating type information regulation 2 homolog 1 (Sirt 1) in the AGE-induced pro-inflammatory toxicity in retinal epithelial cells, we investigated the role of HMGB1 and Sirt 1 in the AGE-induced pro-inflammatory cytokines and chemokines.

RESULTS

It was demonstrated that the expression of TNF-α, IL-1β, IL-6, MCP-1, RANTES and IP-10 was promoted by the AGE-BSA treatment dose-dependently. The treatment with AGE-BSA also significantly promoted the HMGB1 at both mRNA and protein levels, dose-dependently. And in addition, we confirmed that HMGB1 mediated the AGE-induced pro-inflammatory cytokines and chemokines in the AGE-treated ARPE-19 cells. Moreover, we found that the Sirt 1 was downregulated by the AGE-BSA treatment at both mRNA and protein levels in the ARPE-19 cells, dose-dependently. Our further investigation recognized the regulatory role of Sirt 1 in the AGE-promoted pro-inflammatory cytokines and chemokines. The Sirt 1 inhibitor aggravated, whereas the Sirt 1 activator inhibited, the translocation of HMGB1 and the promotion of AGE-induced IL-1β and IL-6.

CONCLUSIONS

Taken together, we confirmed that AGE-BSA promoted HMGB1 but down regulated Sirt 1 in human retinal cells. Sirt 1 was confirmed to regulate AGE-induced pro-inflammatory cytokines and chemokines via inhibiting the nuclear-to-cytoplasmic translocation and release of HMGB1 in retinal ARPE-19 cells.