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Schiffer, Tomas A.
Publications (8 of 8) Show all publications
Christensen, M., Schiffer, T. A., Gustafsson, H., Krag, S. P., Nörregaard, R. & Palm, F. (2019). Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-2. Diabetes/Metabolism Research Reviews, 35(2), Article ID e3091.
Open this publication in new window or tab >>Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-2
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2019 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 35, no 2, article id e3091Article in journal (Refereed) Published
Abstract [en]

Background: The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.

Methods: Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance.

Results: Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.

Conclusions: Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
diabetic kidney disease, metformin, hypoxia
National Category
Endocrinology and Diabetes Physiology
Identifiers
urn:nbn:se:uu:diva-377680 (URN)10.1002/dmrr.3091 (DOI)000457591100002 ()30345618 (PubMedID)
Funder
Swedish Research CouncilErnfors FoundationSwedish Diabetes Association
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Schiffer, T. A., Gustafsson, H. & Palm, F. (2018). Kidney outer medulla mitochondria are more efficient compared with cortex mitochondria as a strategy to sustain ATP production in a suboptimal environment. American Journal of Physiology - Renal Physiology, 315(3), F677-F681
Open this publication in new window or tab >>Kidney outer medulla mitochondria are more efficient compared with cortex mitochondria as a strategy to sustain ATP production in a suboptimal environment
2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 315, no 3, p. F677-F681Article in journal (Refereed) Published
Abstract [en]

The kidneys receive similar to 25% of cardiac output, which is a prerequisite to maintain sufficient glomerular filtration rate. However, both intrarenal regional renal blood flow and tissue oxygen levels are heterogeneous with decreasing levels in the inner part of the medulla. These differences, in combination with the heterogeneous metabolic activity of the different nephron segment located in the different parts of the kidney, may constitute a functional problem when challenged. The proximal tubule and the medullary thick ascending limb of Henle are considered to have the highest metabolic rate, which is related to the high mitochondria content needed to sustain sufficient ATP production from oxidative phosphorylation to support high electrolyte transport activity in these nephron segments. Interestingly, the cells located in kidney medulla function at the verge of hypoxia, and the mitochondria may have adapted to the surrounding environment. However, little is known about intrarenal differences in mitochondria function. We therefore investigated functional differences between mitochondria isolated from kidney cortex and medulla of healthy normoglycemic rats by using high-resolution respirometry. The results demonstrate that medullary mitochondria had a higher degree of coupling, are more efficient, and have higher oxygen affinity, which would make them more suitable to function in an environment with limited oxygen supply. Furthermore, these results support the hypothesis that mitochondria of medullary cells have adapted to the normal hypoxic in vivo situation as a strategy of sustaining ATP production in a suboptimal environment.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
cortex, kidney, medulla, mitochondria, oxygen affinity, P/O ratio
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-364249 (URN)10.1152/ajprenal.00207.2018 (DOI)000444017300015 ()29846107 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationErnfors Foundation
Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-24Bibliographically approved
Schiffer, T. A., Christensen, M., Gustafsson, H. & Palm, F. (2018). The effect of inactin on kidney mitochondrial function and production of reactive oxygen species. PLoS ONE, 13(11), Article ID e0207728.
Open this publication in new window or tab >>The effect of inactin on kidney mitochondrial function and production of reactive oxygen species
2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 11, article id e0207728Article in journal (Refereed) Published
Abstract [en]

Inactin is a long lasting anesthetic agent commonly used in rat studies, but is also shown to exert physiological effects such as reducing renal blood flow, glomerular filtration rate and depressing tubular transport capacity. The effect of inactin on isolated kidney mitochondria is unknown and may be important when studying related topics in anaesthetized animals. The aim of this study was to determine whether inactin exerts effects on mitochondrial function and production of reactive oxygen species. Kidney mitochondrial function and production of reactive oxygen after acutely (5 min) or longer (1.5 hour) anesthetizing rats with inactin was evaluated using high-resolution respirometry. The results demonstrate that inactin significantly improves respiratory control ratio, inhibits complex I in the mitochondrial respiratory chain, reduce both unregulated proton leak and time dependently reduce the regulated proton leak via uncoupling protein-2 and adenine nucleotide translocase. Inactin also contributes to increased mitochondrial hydrogen peroxide production. In conclusion, inactin exerts persistent effects on mitochondrial function and these profound effects on mitochondrial function should to be considered when studying mitochondria isolated from animals anesthesized with inactin.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-372448 (URN)10.1371/journal.pone.0207728 (DOI)000451325700060 ()30475856 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationÅke Wiberg FoundationNovo NordiskSwedish Society for Medical Research (SSMF)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Christensen, M., Schiffer, T. A., Norregaard, R. & Palm, F. (2017). Metformin Normalises Medullary Hypoxia in The Diabetic Rat Kidney. Paper presented at Annual Meeting of the American-Society-for-Pharmacology-and-Experimental-Therapeutics (ASPET) at Experimental Biology Meeting, APR 22-26, 2017, Chicago, IL. The FASEB Journal, 31
Open this publication in new window or tab >>Metformin Normalises Medullary Hypoxia in The Diabetic Rat Kidney
2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-346185 (URN)000405986503342 ()
Conference
Annual Meeting of the American-Society-for-Pharmacology-and-Experimental-Therapeutics (ASPET) at Experimental Biology Meeting, APR 22-26, 2017, Chicago, IL
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Schiffer, T. A. & Friederich-Persson, M. (2017). Mitochondrial Reactive Oxygen Species and Kidney Hypoxia in the Development of Diabetic Nephropathy. Frontiers in Physiology, 8, Article ID 211.
Open this publication in new window or tab >>Mitochondrial Reactive Oxygen Species and Kidney Hypoxia in the Development of Diabetic Nephropathy
2017 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 211Article, review/survey (Refereed) Published
Abstract [en]

The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2017
Keywords
diabetic nephropathy, kidney hypoxia, mitochondrial function, superoxide production, mitochondrial uncoupling, mitochondrial ROS, hypoxia inducible factors
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-321837 (URN)10.3389/fphys.2017.00211 (DOI)000398718900001 ()28443030 (PubMedID)
Funder
Wenner-Gren Foundations
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-01-13Bibliographically approved
Carvalho, C., Schiffer, T. A., Zheng, X.-W., Grünler, J., Karlsson, S., Mazzone, M., . . . Palm, F.Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic mice.
Open this publication in new window or tab >>Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic mice
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387385 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23
Carvalho, C., Schiffer, T. A., Zheng, X.-W., Grünler, J., Karlsson, S., Mazzone, M., . . . Palm, F.Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice.
Open this publication in new window or tab >>Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387387 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23
Carvalho, C., Schiffer, T. A., Karlsson, S., Hansell, P., Friederich, M. & Palm, F.Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretion.
Open this publication in new window or tab >>Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretion
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387388 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23
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