Palm 2013 Abstract MiP2013

Palm F, Hansell P, Friederich-Persson M(2013) Role of mitochondria function for the onset and progression of kidney disease. Mitochondr Physiol Network 18.08.

Link:

Palm F, Hansell P, Friederich-Persson M (2013)

Event: MiP2013

Diabetes is closely associated with increased oxidative stress, especially from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondrial membrane potential by releasing protons across the mitochondrial membrane. This phenomenon is referred to as mitochondrial uncoupling since oxygen is consumed independently of ATP being produced, and can be mediated by uncoupling proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy.

UCP-2 is the only isoform expressed in the kidney, and localized to the tubular segment performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetic rats have increased UCP-2 protein expression which correlates to increased non-transport dependent oxygen in isolated proximal tubular cells. These effects are prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increases mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the mitochondrial targeting antioxidant coenzyme Q10 prevents mitochondrial uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increases mitochondrial uncoupling via a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreases mitochondrial membrane potential and kidney oxidative stress but does not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension. The role of increased mitochondrial oxygen consumption per se has been demonstrated by administering the chemical uncoupler dinitrophenol to otherwise healthy rats. Importantly, increased mitochondrial oxygen consumption results in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin demonstrating a crucial role of increased oxygen consumption and the resulting kidney tissue hypoxia for the development of nephropathy.

Taken together, these observations demonstrate an important and pivotal role of mitochondrial uncoupling for the development of chronic kidney disease.

• O2k-Network Lab: SE Uppsala Liss P

Labels: Pathology: Diabetes  Stress:Hypoxia, RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Mouse, Rat  Tissue;cell: Kidney  Preparation: Intact Organ"Intact Organ" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property., Intact Cell; Cultured; Primary"Intact Cell; Cultured; Primary" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property., Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: Adenine Nucleotide Translocase"Adenine Nucleotide Translocase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property., Uncoupling protein 

Coupling state: LEAK 

HRR: Oxygraph-2k 

Affiliations and author contributions

1 - Dept of Medical Cell Biology, Uppsala University, Sweden;

2 - Dept of Medical and Health Sciences, Linköping University, Sweden;

3 - Center for Medical Image Science and Visualization, Linköping University, Sweden.

Email: [email protected]; [email protected]