RANKL / OPG signalling activities at rat models forming diet Induced endothelial dysfunction

Endothelial injury is the one of the beginning pathology of several diseases such as atherosclerosis and diabetes. Nuclear factor κB (NF-κB) signalling pathway plays an important role in endothelial damage. Receptor Activator NF-κB Ligand (RANKL) and its receptor RANK and Osteoprotegerin (OPG) are known as the determinants of calcification as a result of damage in endothelium. It is known that the OPG/RANK/RANKL pathway plays a role in the skeletal, inflammation, and vascular system. In the experimental studies, strong data have been obtained that OPG pathway regulates glucose homeostasis, therefore there is a strong relationship between OPG and Type 2 Diabetes Mellitus (T2DM). Although plasma RANKL/OPG levels have been shown in atherosclerosis by transgenic studies, their role in vascular diseases is not known yet. In this thesis, it was aimed to obtain preliminary information that could contribute to both preventions of endothelial damage and determination of new treatment goals. For this purpose, male Sprague Dawley rats were used to make Type 2 Diabetes Mellitus Model and the role of RANKL/OPG pathway in endothelial damage is studied. Endothelial damage-dependent microvascular analysis is analysed by using gene expression of Opg, Rankl, Runx2, Bmp-2, Il-1ß, Tnfα, Nos3, Icam-1. In diabetic rats, Opg, Il-1ß, Bmp2 expression levels increase significantly while mRNA level of Icam-1 and Nos3 as markers of endothelial damage show also a significant correlation with elevation of mRNA level of Opg. In addition, effect of vitamin D3 which is one of the regulators in the OPG/RANKL pathway on the gene expression were studied in the presence of diabetes. After 4 weeks, blood sugar levels significantly increased (p <0.001) in diabetic rats compared to other experimental groups. In the aortic endothelial cells of diabetic rats, vitamin D3 administration it was observed significant difference in expression levels of the Opg and Il-1b gene. This study shows that vitamin D supplementation effect on OPG/RANKL activity in the vessel wall. These study results provide the first evidence that Vitamin D3 supplementation results in ameliorated endothelial damage in type 2 diabetes mellitus, and that OPG plays a crucial role in the regulation of cytokines mediating vascular homeostasis.