Functional role of HIF-1-regulated pathway in diabetic nephropathy

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...