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Abstract
Master Thesis, Programme in Medicine
Mitochondrial uncoupling reduces kidney concentrations of glucose and glycogen and
induces kidney damage – possible relevance to diabetic nephropathy?
Erik Thörn, 2012
Wallenberg Laboratory, Gothenburg, Sweden
Introduction - Diabetes is a common metabolic disease with severe complications. One of the
most important complications is kidney damage. One dominating hypothesis is that diabetic
kidney damage is secondary to oxidative stress due to hyperglycemia. An alternate hypothesis is
that mitochondrial uncoupling promotes kidney damage. Mitochondria from diabetic rats have
increased levels of uncoupling protein-2.
Aim - To investigate if increased mitochondrial uncoupling induces kidney damage and how it
affects kidney energy metabolism.
Methods – Rats were either treated with a chemical uncoupler, 2,4-dinitrophenol, or vehicle. The
effect of DNP-treatment on kidney oxygen consumption, tubular injury, inflammation and
hypoxia was analyzed. Bioluminescence imaging was used to visualize and quantify the
distribution of ATP, glucose, glucose-6-phosphate and glycogen in cryosections from their kidney
tissue.
Results – DNP-treatment induced increased oxygen consumption, tubular injury, infiltration of
immune cells and mRNA levels of genes related to hypoxia. Energy metabolites were
heterogeneously distributed between the cortex and medulla. ATP levels were higher in the
medulla than in the cortex, indicating higher metabolic activity. In agreement, energy substrates
glucose and glycogen showed the opposite pattern with lower concentrations in the medulla,
indicating high local consumption. DNP-treatment did not affect ATP levels but decreased
glycogen levels in both the cortex and medulla of the kidney. Similarly, glucose was significantly
lower in the cortex and borderline significant in the medulla.
Conclusions - Mitochondrial uncoupling induces kidney damage while decreasing levels of
extracellular (glucose) and intracellular (glycogen) glucose. This provides support for the
hypothesis that hyperglycemia independent hypermetabolism may promote diabetic kidney
damage.
Keywords – Energy metabolism – Uncoupling – Kidney damage – 2,4-dinitrophenol.