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Diabetes-induced mitochondrial changes are tissue- and model-dependent and elevated glucose levels do not activate the pathways of hyperglycemic damage in the kidney

Volk, Nadine

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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.

Item Type: Dissertation
Supervisor: Nawroth, Prof. Dr. Peter Paul
Date of thesis defense: 2 May 2018
Date Deposited: 29 May 2018 08:20
Date: 2018
Faculties / Institutes: Medizinische Fakultät Heidelberg > Medizinische Universitäts-Klinik und Poliklinik
Subjects: 500 Natural sciences and mathematics
610 Medical sciences Medicine
Controlled Keywords: Diabetes mellitus, Mitochondrium, Nephropathia diabetica
Uncontrolled Keywords: Reaktive Sauerstoffspezies Unifying Theory
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