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Palm, Fredrik
Publications (10 of 104) 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
Eckerbom, P., Hansell, P., Cox, E. F., Buchanan, C., Weis, J., Palm, F., . . . Liss, P. (2019). Multiparametric assessment of renal physiology in healthy volunteers using non-invasive magnetic resonance imaging. American Journal of Physiology - Renal Physiology, 316(4), F693-F702
Open this publication in new window or tab >>Multiparametric assessment of renal physiology in healthy volunteers using non-invasive magnetic resonance imaging
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2019 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 4, p. F693-F702Article in journal (Refereed) Published
Abstract [en]

Non-invasive methods of magnetic resonance imaging (MRI) can quantify parameters of kidney function. The main purpose of this study was to determine baseline values of such parameters in healthy volunteers. In 28 healthy volunteers (15 females, 13 males), Arterial Spin Labeling (ASL) to estimate regional renal perfusion, Blood Oxygen Level Dependent (BOLD) transverse relaxation rate (R2*) to estimate oxygenation, and Apparent Diffusion Coefficient (ADC), true diffusion (D) and longitudinal relaxation time (T1) to estimate tissue properties were determined bilaterally in the cortex, outer and inner medulla. Additionally, phase contrast (PC) MRI was applied in the renal arteries to quantify total renal blood flow. The results demonstrated profound gradients of perfusion, ADC and D with highest values in the kidney cortex and a decrease towards the inner medulla. R2* and T1 were lowest in kidney cortex and increased towards the inner medulla. Total renal blood flow correlated with body surface area, body mass index and renal volume. Similar patterns in all investigated parameters were observed in females and males. In conclusion, non-invasive MRI provides useful tools to evaluate intra renal differences in blood flow, perfusion, diffusion, oxygenation and structural properties of the kidney tissue. As such, this experimental approach has the potential to advance our current understanding regarding normal physiology and the pathological processes associated with acute and chronic kidney disease.

Keywords
ASL, BOLD, Diffusion, Kidney, MRI
National Category
Radiology, Nuclear Medicine and Medical Imaging Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-374891 (URN)10.1152/ajprenal.00486.2018 (DOI)30648907 (PubMedID)
Funder
Swedish Diabetes AssociationSwedish Child Diabetes FoundationSwedish Research Council
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-04-17Bibliographically approved
Qi, H., Nielsen, P. M., Schroeder, M., Bertelsen, L. B., Palm, F. & Laustsen, C. (2018). Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats. Diabetologia, 61(2), 445-454
Open this publication in new window or tab >>Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 2, p. 445-454Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver. This inhibition alters cytosolic and mitochondrial reduction–oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes.

Methods

Diabetes was induced by intravenous injection of streptozotocin, and kidney metabolism in healthy and diabetic animals was investigated 4 weeks thereafter using hyperpolarised 13C-MRI, Clark-type electrodes and biochemical analysis.

Results

Metformin increased renal blood flow, but did not change total kidney oxygen consumption. In healthy rat kidneys, metformin increased [1-13C]lactate production and reduced mitochondrial [1-13C]pyruvate oxidation (decreased the 13C-bicarbonate/[1-13C]pyruvate ratio) within 30 min of administration. Corresponding alterations to indices of mitochondrial, cytosolic and whole-cell redox potential were observed. Pyruvate oxidation was maintained in the diabetic rats, suggesting that the diabetic state abrogates metabolic reprogramming caused by metformin.

Conclusions/interpretation

This study demonstrates that metformin-induced acute metabolic alterations in healthy kidneys favoured anaerobic metabolism at the expense of aerobic metabolism. The results suggest that metformin directly alters the renal redox state, with elevated renal cytosolic redox states as well as decreased mitochondrial redox state. These findings suggest redox biology as a novel target to eliminate the renal complications associated with metformin treatment in individuals with impaired renal function.

Keywords
Diabetes, Hyperpolarised MRI, Metformin, Renal function, Renal metabolism, Renal redox
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-341483 (URN)10.1007/s00125-017-4445-6 (DOI)000419011600019 ()28936623 (PubMedID)
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved
Friederich, M., Persson, P., Hansell, P. & Palm, F. (2018). Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes. Acta Physiologica, 223(4), Article ID e13058.
Open this publication in new window or tab >>Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes
2018 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 223, no 4, article id e13058Article in journal (Refereed) Published
Abstract [en]

AimUncoupling protein-2 (UCP-2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP-2(-/-) mice, we tested the hypothesis that UCP-2-mediated leak respiration is important for the development of diabetes-induced intrarenal hypoxia and proteinuria. MethodsKidney function, invivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild-type and UCP-2(-/-) mice during normoglycaemia and 2weeks after diabetes induction. ResultsDiabetic wild-type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM-1 excretion. However, diabetic UCP-2(-/-) mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM-1 excretion. ConclusionAlthough functioning as an antioxidant system, mitochondria uncoupling is always in co-occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP-2-mediated mitochondrial leak respiration is necessary for the development of diabetes-induced intrarenal tissue hypoxia and proteinuria.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
diabetic nephropathy, kidney, kidney injury molecule-1, mitochondria, oxygen consumption
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-361674 (URN)10.1111/apha.13058 (DOI)000438491300002 ()29480974 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Diabetes Association
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Palm, F. & Koeners, M. P. (2018). Editorial: Hypoxia in Kidney Disease. Frontiers in Physiology, 9, Article ID 485.
Open this publication in new window or tab >>Editorial: Hypoxia in Kidney Disease
2018 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 485Article in journal, Editorial material (Other academic) Published
Keywords
kidney hypoxia, chronic kidney disease, hypertension, magnetic resonance imaging, mitochondrial uncoupling, telemetry, kidney transplantation, sympathetic nerve activity
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-357650 (URN)10.3389/fphys.2018.00485 (DOI)000431346300001 ()
Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2018-08-28Bibliographically approved
Sivertsson, E., Friederich Persson, M., Öberg, C. M., Fasching, A., Hansell, P., Rippe, B. & Palm, F. (2018). Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability. American Journal of Physiology - Renal Physiology, 314(5), F864-F872
Open this publication in new window or tab >>Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability
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2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 5, p. F864-F872Article in journal (Refereed) Published
Abstract [en]

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
glomerular permeability, hypoxia, mitochondrial function, mTOR, oxygen consumption, tubular injury
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-363076 (URN)10.1152/ajprenal.00033.2017 (DOI)000441089200019 ()28971989 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Society for Medical Research (SSMF)
Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved
Franzén, S., Pihl, L., Fasching, A. & Palm, F. (2018). Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats. American Journal of Physiology - Renal Physiology, 314(3), F439-F444
Open this publication in new window or tab >>Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats
2018 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, no 3, p. F439-F444Article in journal (Refereed) Published
Abstract [en]

About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
diabetes, endothelin, kidney, oxygen consumption, oxygen tension
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-354369 (URN)10.1152/ajprenal.00498.2017 (DOI)000428517700014 ()29092848 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationSwedish Diabetes AssociationErnfors Foundation
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically 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
Nilsson, L., Palm, F. & Nørregaard, R. (2017). 15-Deoxy-Delta(12,14)-prostaglandin J(2) Exerts Antioxidant Effects While Exacerbating Inflammation in Mice Subjected to Ureteral Obstruction. Mediators of Inflammation, Article ID 3924912.
Open this publication in new window or tab >>15-Deoxy-Delta(12,14)-prostaglandin J(2) Exerts Antioxidant Effects While Exacerbating Inflammation in Mice Subjected to Ureteral Obstruction
2017 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 3924912Article in journal (Refereed) Published
Abstract [en]

Urinary obstruction is associated with inflammation and oxidative stress, leading to renal dysfunction. Previous studies have shown that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has both antioxidant and anti-inflammatory effects. Using a unilateral ureteral obstruction (UUO) mouse model, we examined the effects of 15d-PGJ(2) on oxidative stress and inflammation in the kidney. Mice were subjected to UUO for 3 days and treated with 15d-PGJ(2). Protein and RNA expression were examined using immunoblotting and qPCR. 15d-PGJ(2) increased NF-E2-related nuclear factor erythroid-2 (Nrf2) protein expression in response to UUO, and heme oxygenase 1 (HO-1), a downstream target of Nrf2, was induced by 15d-PGJ(2). Additionally, 15d-PGJ(2) prevented protein carbonylation, a UUO-induced oxidative stress marker. Inflammation, measured by nuclear NF-kappa B, F4/80, and MCP-1, was increased in response to UUO and further increased by 15d-PGJ(2). Renal injury was aggravated by 15d-PGJ(2) treatment as measured by kidney injury molecule-1 (KIM-1) and cortical caspase 3 content. No effect of 15d-PGJ(2) was observed on renal function in mice subjected to UUO. This study illustrates differentiated functioning of 15d-PGJ(2) on inflammation and oxidative stress in response to obstructive nephropathy. High concentrations of 15d-PGJ(2) protects against oxidative stress during 3-day UUO in mice; however, it aggravates the associated inflammation.

Place, publisher, year, edition, pages
HINDAWI LTD, 2017
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-322117 (URN)10.1155/2017/3924912 (DOI)000399497400001 ()28503033 (PubMedID)
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2018-01-13Bibliographically approved
Laustsen, C., Nielsen, P. M., Nørlinger, T. S., Qi, H., Pedersen, U. K., Bertelsen, L. B., . . . Stødkilde-Jørgensen, H. (2017). Antioxidant treatment attenuates lactate production in diabetic nephropathy. American Journal of Physiology - Renal Physiology, 312(1), F192-F199
Open this publication in new window or tab >>Antioxidant treatment attenuates lactate production in diabetic nephropathy
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2017 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 1, p. F192-F199Article in journal (Refereed) Published
Abstract [en]

The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-(13)C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned (13)C/(1)H-volume rat coil. The rats received intravenous hyperpolarized [1-(13)C]pyruvate and were imaged using a slice-selective (13)C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [(13)C]alanine levels, indicating an intact glucose-alanine cycle, or [(13)C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.

Keywords
MRI, TEMPOL, diabetic nephropathy, hyperpolarization, renal metabolism
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-318082 (URN)10.1152/ajprenal.00148.2016 (DOI)000393897600018 ()28069660 (PubMedID)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-01-13Bibliographically approved
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