Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages

• Published in: Redox biology 2018-05, Vol.15 (C), p.170-181
• Main Authors: Prattichizzo, Francesco, De Nigris, Valeria, Mancuso, Elettra, Spiga, Rosangela, Giuliani, Angelica, Matacchione, Giulia, Lazzarini, Raffaella, Marcheselli, Fiorella, Recchioni, Rina, Testa, Roberto, La Sala, Lucia, Rippo, Maria Rita, Procopio, Antonio Domenico, Olivieri, Fabiola, Ceriello, Antonio
• Format: Article
• Language: English
• Subjects: Animals; Anion superoxide; Cellular Senescence - genetics; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Endothelial cells; Endothelial Cells - pathology; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; Humans; Hyperglycemia - complications; Hyperglycemia - genetics; Hyperglycemia - metabolism; Hyperglycemia - pathology; Inflammation; Inflammation - complications; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Kidney - metabolism; Kidney - pathology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Macrophages; Macrophages - metabolism; Macrophages - pathology; Mice; Phenotype; Research Paper; Senescence associated secretory phenotype; Superoxide Dismutase-1 - genetics
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2017.12.001

Diabetic status is characterized by chronic low-grade inflammation and an increased burden of senescent cells. Recently, the senescence-associated secretory phenotype (SASP) has been suggested as a possible source of inflammatory factors in obesity-induced type 2 diabetes. However, while senescence is a known consequence of hyperglycaemia, evidences of SASP as a result of the glycaemic insult are missing. In addition, few data are available regarding which cell types are the main SASP-spreading cells in vivo. Adopting a four-pronged approach we demonstrated that: i) an archetypal SASP response that was at least partly attributable to endothelial cells and macrophages is induced in mouse kidney after in vivo exposure to sustained hyperglycaemia; ii) reproducing a similar condition in vitro in endothelial cells and macrophages, hyperglycaemic stimulus largely phenocopies the SASP acquired during replicative senescence; iii) in endothelial cells, hyperglycaemia-induced senescence and SASP could be prevented by SOD-1 overexpression; and iiii) ex vivo circulating angiogenic cells derived from peripheral blood mononuclear cells from diabetic patients displayed features consistent with the SASP. Overall, the present findings document a direct link between hyperglycaemia and the SASP in endothelial cells and macrophages, making the SASP a highly likely contributor to the fuelling of low-grade inflammation in diabetes. •Hyperglycaemia induces senescence and the SASP in endothelial cells and macrophages in vivo.•Hyperglycaemia-induced senescence phenocopies replicative senescence in endothelial cells.•Overexpression of SOD-1 blunts hyperglycaemia-induced endothelial senescence and SASP.•Macrophages exposed to hyperglycaemia develop senescence and SASP markers.•Circulating angiogenic cells from T2DM patients show increased senescence and SASP mRNAs.