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Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
2013 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, 217-223 p.Article in journal (Refereed) Published
Abstract [en]

Kidney uncoupling protein 2 (UCP-2) increases in streptozotocin-induced diabetes, resulting in mitochondria uncoupling, i.e., increased oxygen consumption unrelated to active transport. The present study aimed to investigate the role of UCP-2 for normal and diabetic kidney function utilizing small interference RNA (siRNA) to reduce protein expression. Diabetic animals had increased glomerular filtration rate and kidney oxygen consumption, resulting in decreased oxygen tension and transported sodium per consumed oxygen. UCP-2 protein levels decreased 2 and 50% after UCP-2 siRNA administration in control and diabetic animals respectively. Kidney function was unaffected by in vivo siRNA-mediated gene silencing of UCP-2. The reason for the lack of effect of reducing UCP-2 is presently unknown but may involve compensatory mitochondrial uncoupling by the adenosine nucleotide transporter.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2013. Vol. 765, 217-223 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-167783DOI: 10.1007/978-1-4614-4989-8_30ISI: 000339280100031ISBN: 978-1-4614-4771-9 (print)ISBN: 978-1-4614-4989-8 (print)OAI: oai:DiVA.org:uu-167783DiVA: diva2:488017
Available from: 2012-02-01 Created: 2012-02-01 Last updated: 2017-12-08
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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Persson, Malou FriederichPalm, Fredrik

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