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.
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.
Authors: Ioannis Gkouveris; Danny Hadaya; Naseim Elzakra; Akrivoula Soundia; Olga Bezouglaia; Sarah M Dry; Flavia Pirih; Tara Aghaloo; Sotirios Tetradis Journal: J Bone Miner Res Date: 2022-07-11 Impact factor: 6.390