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Abstract
It is commonly accepted that oxidative stress, caused by increased metabolic flux and subsequent activation of the four major pathways of hyperglycemic damage are a causative factor for the development of diabetic nephropathy. However, therapies inactivating these pathways do not improve the symptoms of nephropathy. As such it was analysed, whether oxidative stress is present at the onset of nephropathy. Streptozotocin-induced diabetic mice (BL6-STZ) and genetically diabetic db/db mice, characterized by incipient albuminuria, were screened for the effects of hyperglycaemia on mitochondrial function, ROS production and the activation of the major pathways of hyperglycaemic damage in the kidney. Despite increased intracellular glucose, substrates of the tricarboxylic cycle were not increased. ATP production and mitochondrial oxygen consumption were increased in the BL6-STZ model, whereas mitochondrial oxygen consumption was decreased in the db/db model. This was not associated with either increased oxidative stress or activation of the protein kinase C and advanced glycation endproduct pathways. The polyol and the hexosamine pathways were increased in the BL6-STZ model but decreased in the db/db model. These differences, despite increased intracellular glucose, could not explain the symptoms of nephropathy. The finding that the Nrf2-NQO1 axis was increased in both models would suggest that the onset of nephropathy is associated with ROS-independent cellular stress.
Dokumententyp: | Dissertation |
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Erstgutachter: | Nawroth, Prof. Dr. Peter Paul |
Tag der Prüfung: | 2 Mai 2018 |
Erstellungsdatum: | 29 Mai 2018 08:20 |
Erscheinungsjahr: | 2018 |
Institute/Einrichtungen: | Medizinische Fakultät Heidelberg und Uniklinikum > Medizinische Universitäts-Klinik und Poliklinik |
DDC-Sachgruppe: | 500 Naturwissenschaften und Mathematik
610 Medizin |
Normierte Schlagwörter: | Diabetes mellitus, Mitochondrium, Nephropathia diabetica |
Freie Schlagwörter: | Reaktive Sauerstoffspezies Unifying Theory |