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Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
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2008 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, Vol. 1777, no 7-8, 935-940 p.Article in journal (Refereed) Published
Description
Abstract [en]

We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.

Place, publisher, year, edition, pages
2008. Vol. 1777, no 7-8, 935-940 p.
Keyword [en]
Diabetes mellitus, kidney, mitochondria, uncoupling protein-2, oxygen consumption
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-110142DOI: 10.1016/j.bbabio.2008.03.030ISI: 000257696400054PubMedID: 18439413OAI: oai:DiVA.org:uu-110142DiVA: diva2:275360
Note
Conference Information: 15th European Bioenergetic Conference Trinity Coll, Dublin, IRELAND, JUL 19-24, 2008 Available from: 2009-11-04 Created: 2009-11-04 Last updated: 2017-03-23Bibliographically approved
In thesis
1. The Role of Mitochondrial Uncoupling in the Development of Diabetic Nephropathy
Open this publication in new window or tab >>The Role of Mitochondrial Uncoupling in the Development of Diabetic Nephropathy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria 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 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased 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 antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension.

     The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy.

     Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 738
Keyword
Kidney, mitochondria, Uncoupling Protein-2, Adenosine Nucleotide Transporter, uncoupling, diabetes, diabetic nephropathy, db/db, dinitrophenol, Coenzyme Q10, oxygen, rats, mice
National Category
Physiology
Research subject
Physiology; Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-167815 (URN)978-91-554-8266-4 (ISBN)
Public defence
2012-03-16, B42, Biomedical Center, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-02-24 Created: 2012-02-01 Last updated: 2012-03-01Bibliographically approved

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