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

Redox Biol. 2018 May;15:170-181. doi: 10.1016/j.redox.2017.12.001. Epub 2017 Dec 6.

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.

Keywords: Anion superoxide; Diabetes; Endothelial cells; Inflammation; Macrophages; Senescence associated secretory phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Senescence / genetics*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Endothelial Cells / pathology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Humans
  • Hyperglycemia / complications
  • Hyperglycemia / genetics*
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Inflammation / complications
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kidney / metabolism
  • Kidney / pathology
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Phenotype
  • Superoxide Dismutase-1 / genetics

Substances

  • Sod1 protein, mouse
  • Superoxide Dismutase-1