The possible link between high glucose-induced PKCβ expression and the appearance of GLP-1 resistance in endothelial cells
[eng] INTRODUCTION. It has been demonstrated that Glucagon-like peptide-1 (GPL-1) has a protective effect on endothelial cells. GLP-1 improves endothelial function in diabetes, however the mechanisms underlying the GLP-1 protective effects have not yet been fully elucidated. Additionally, it has bee...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2015 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/68388 |
| Acesso em linha: | https://hdl.handle.net/2445/68388 http://tdx.cat/handle/10803/325682 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Diabetis Hiperglucèmia Endoteli Diabetes Hyperglycemia Endothelium |
| Resumo: | [eng] INTRODUCTION. It has been demonstrated that Glucagon-like peptide-1 (GPL-1) has a protective effect on endothelial cells. GLP-1 improves endothelial function in diabetes, however the mechanisms underlying the GLP-1 protective effects have not yet been fully elucidated. Additionally, it has been proposed that GLP-1 could restore high glucose - endoplasmic reticulum (ER) stress induction. Recent evidences claim a resistance of GLP-1 action that has been shown in pancreatic 13-cells of diabetic patients. A proposed mechanism to explain this resistance to the GLP-1 action in diabetes is the activation of PKCI3, induced by hyperglycaemia, which is able to reduce the expression of GLP-1 receptor. AIM. The aim of this thesis project was to decipher if GLP-1 acute treatment is able to counteract chronic high glucose-induced damage in Human umbilical Vein Endothelial cells (HUVECs). METHODS. In this study HUVECs were cultured for 21 days under normal glucose (5mmol/L, NG) or high glucose (25mmol/L glucose, HG) concentrations. GLP-1 and Ruboxistaurin were added alone or in combination, 1 hour before cell harvesting. Analysis of GLP-1 receptor protein levels as well as of gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes and PKA subunits was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. RESULTS. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations and it was partially restored after treatment with the chemical PKCI3 specific inhibitor, Ruboxistaurin. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of detoxifying enzymes Nrf2 targets, to increase transcript levels of scavenger genes, to attenuate the high glucose-induced PKA subunits expression, ER stress and also the apoptotic phenotype of HUVECs only when high glucose-induced PKCI3 overexpression was reduced by Ruboxistaurin. In the same direction, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCI3 inhibitor. CONCLUSIONS. This study suggests that PKCI3 increase, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting GLP-1 canonical pathway. |
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