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Functional role of HIF-1-regulated pathway in diabetic nephropathy
Nepomucká, Kateřina ; Konvalinka, Jan (advisor) ; Jonáková, Věra (referee)
Diabetic nephropathy (DN) remains the most common cause of end stage renal failure. Nearly 10% of patients with diabetes develop nephropathy. Hyperglycaemia in the kidneys leads to the activation of alternative metabolic pathways of glucose (glycation, activation of protein kinase C, and polyol pathway). These biochemical alterations lead to hypoxia and oxidative stress due to the increased formation of reactive oxygen species (ROS). Cellular response to hypoxia is controlled by hypoxia-induced factor 1 (HIF1), which is involved in the regulation of more than 800 genes. Target molecules of the HIF1 pathway participate in a wide range of physiological and pathological processes, e.g. angiogenesis, energy metabolism, apoptosis, migration, and proliferation. DN is associated with the pathological tissue remodelling process, epithelial-mesenchymal transition (EMT), and inflammation. HIF1 regulates key molecules of these pathological processes. EMT is regulated by TGFß1, CTGF, and SOX9. The progression of inflammation is regulated by VEGFA and AngII. The exact role of HIF1 signalling in the development of DN is not yet fully understood. This thesis evaluates the functional role of the HIF1 signalling pathway in the development of DN using a global heterozygous mutant with the deletion of the Hif1α gene....
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Functional role of HIF-1-regulated pathway in diabetic nephropathy
Nepomucká, Kateřina ; Konvalinka, Jan (advisor) ; Jonáková, Věra (referee)
Diabetic nephropathy (DN) remains the most common cause of end stage renal failure. Nearly 10% of patients with diabetes develop nephropathy. Hyperglycaemia in the kidneys leads to the activation of alternative metabolic pathways of glucose (glycation, activation of protein kinase C, and polyol pathway). These biochemical alterations lead to hypoxia and oxidative stress due to the increased formation of reactive oxygen species (ROS). Cellular response to hypoxia is controlled by hypoxia-induced factor 1 (HIF1), which is involved in the regulation of more than 800 genes. Target molecules of the HIF1 pathway participate in a wide range of physiological and pathological processes, e.g. angiogenesis, energy metabolism, apoptosis, migration, and proliferation. DN is associated with the pathological tissue remodelling process, epithelial-mesenchymal transition (EMT), and inflammation. HIF1 regulates key molecules of these pathological processes. EMT is regulated by TGFß1, CTGF, and SOX9. The progression of inflammation is regulated by VEGFA and AngII. The exact role of HIF1 signalling in the development of DN is not yet fully understood. This thesis evaluates the functional role of the HIF1 signalling pathway in the development of DN using a global heterozygous mutant with the deletion of the Hif1α gene....
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Gene expression profiling in diabetic nephropathy
Nepomucká, Kateřina ; Pavlínková, Gabriela (advisor) ; Černá, Věra (referee)
Diabetic nephropathy (DN) is induced by both type 1 and type 2 diabetes mellitus and it is one of the most serious complications associated with diabetes. Despite increasing incidence of diabetes, the exact pathogenesis remains unclear. Hypoxia is regarded as a crucial factor for the progression of renal disease. The responses to hypoxia are mainly regulated by hypoxia-inducible factor 1 (HIF1). We thus considered a possible link between HIF1-regulated pathways and the susceptibility to DN and the disease progression. We hypothesize that the exposure of renal tissue to diabetes causes gene expression changes in HIF1-regulated pathway and the altered expression profile is decisive for the development of DN. Using mouse model, we analyzed cellular and molecular changes in HIF1 heterozygous-null (Hif1α+/- ) and wild type (wt) littermates exposed to diabetic environment. Our histological analysis showed early pathological changes associated with DN in both diabetic wt and Hif1α+/- compared to non-diabetic controls. The morphological analysis did not demonstrate the effect of Hif1α+/- genotype in comparison to wt. For our molecular analysis with qRT-PCR method, we selected several genes, which were previously associated with pathological processes in kidney diseases. We identified statistically...
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