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

Abstract

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.

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…Similar results were later reproduced with various T2DM mouse models . However, because control animals were not treated with glucose‐lowering agents, it is not known whether these effects are the result of the specific activity of SGLT2 inhibitors or reflect the effective amelioration of hyperglycaemia, which, per se , fosters LGI . An elegant study showed that peritoneal macrophages secrete IL‐1β in a glucose‐dependent manner in response to feeding and post‐prandial glycaemic spikes.…”

“…[55][56][57][58][59] However, because control animals were not treated with glucose-lowering agents, it is not known whether these effects are the result of the specific activity of SGLT2 inhibitors or reflect the effective amelioration of hyperglycaemia, which, per se, fosters LGI. 32,60 An elegant study showed that peritoneal macrophages secrete IL-1β in a glucose-dependent manner in response to feeding and post-prandial glycaemic spikes. IL-1β stimulates insulin secretion, and together they act on macrophages to induce glucose uptake, and insulin sustains a pro-inflammatory gene expression profile.…”

Kallistatin attenuates endothelial senescence by modulating Let‐7g‐mediated miR‐34a‐SIRT1‐eNOS pathway

“…Catalase, one of SIRT1's downstream antioxidant enzymes, is decreased in H 2 O 2 ‐induced premature senescence . Human SOD‐2 and mouse SOD‐1 are antioxidant enzymes and play an important role in the prevention of endothelial senescence and inflammation . Previous reports indicated a reciprocal positive feedback regulation between SIRT1 and eNOS .…”

Where Metabolism Meets Senescence: Focus on Endothelial Cells

“…Increasing evidence is suggesting a bidirectional interplay among EC metabolism and ARDs (Graupera and Claret, 2018). One of the most characterized metabolic alteration in ECs exposed to hyperglycemia, i.e., a known senescencepromoting stimulus (Prattichizzo et al, 2018a), is the diversion of glycolytic intermediates into alternate pathways (Figure 2). This is the result of the activation of the enzyme polyADP-ribose polymerase 1 (PARP1) following the ROS-induced DNA damage.…”