Evans, M.A.; (2009) Annexin 2 and diabetic vascular disease. Doctoral thesis , UCL (University College London).

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Abstract

Diabetes affects around 2.3 million people in the UK and can lead to both acute and chronic complications. One of the chronic effects of diabetes is the damage that occurs to the vascular endothelium, affecting multiple organ systems, collectively termed diabetic vascular disease. Many proteins have been identified as being altered in diabetes, one of which is annexin 2, a calcium dependent phospholipid binding protein involved in many cellular processes. In response to diabetes annexin 2 is enriched on the surface of the endothelium where it functions as a co-receptor for tissue plasminogen activator and plasminogen to form plasmin, creating a pro-fibrinolytic environment. This thesis aimed to further examine the role of annexin 2 in diabetes, utilising the annexin 2 knockout mouse in both in vitro and in vivo experiments. As part of our in vitro experiments, we identified a hyperglycaemic translocation of annexin 2 to alternative cellular compartments, using sucrose density centrifugation, and an increased susceptibility of VE-cadherin to destabilisation upon the action of vascular endothelial growth factor in annexin 2 knockout endothelial cells. In the in vivo experiments we utilised streptozotocin to induce diabetes in the annexin 2 knockout mouse, and examined the progression of both diabetic retinopathy and diabetic nephropathy. Annexin 2 knockout mice developed more severe symptoms of diabetic nephropathy with increased microalbuminuria, mesenchymal matrix expansion and histological changes indicative of renal disease. In contrast to this, symptoms pertaining to diabetic retinopathy were mild in all mice. Non-diabetic annexin 2 knockout mice also exhibited mild hypoglycaemia, potentially implicating defects in the insulin signalling pathway, and suggesting a novel role for annexin 2 in glucose homeostasis.

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