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Palm, Fredrik
Publications (10 of 101) Show all publications
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
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
Persson, P., Fasching, A., Teerlink, T., Hansell, P. & Palm, F. (2017). Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity. American Journal of Physiology - Renal Physiology, 312(2), F278-F283
Open this publication in new window or tab >>Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity
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2017 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 2, p. F278-F283Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of L-arginine is rate limiting for nitric oxide production, and that plasma L-arginine concentration is decreased in diabetes. We therefore investigated if regional renal blood flow regulation is affected by cellular L-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital and left kidney was exposed. Total, cortical and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either L-homoarginine to inhibit cellular uptake of L-arginine, or L-NAME to inhibit nitric oxide synthase. L-homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. L-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both L-homoarginine and L-NAME were more pronounced in the control groups compared to the diabetic groups. Isolated cortical tubular cells displayed similar L-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased L-arginine uptake capacity. Diabetics had reduced L-arginine concentrations in plasma and medullary tissue but increased L-arginine concentration in cortical tissue. In conclusion, the reduced L-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular L-arginine and the upregulated cortical tissue L-arginine may protect cortical hemodynamics in diabetes.

Keywords
L-homoarginine, cortical blood flow, kidney, renal blood flow, streptozotocin
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-310400 (URN)10.1152/ajprenal.00335.2016 (DOI)000393897900006 ()27927650 (PubMedID)
Funder
Swedish Research CouncilÅke Wiberg FoundationSwedish Society for Medical Research (SSMF)Swedish Diabetes Association
Available from: 2016-12-15 Created: 2016-12-15 Last updated: 2018-01-13Bibliographically approved
Juul, T., Palm, F., Nielsen, P. M., Bertelsen, L. B. & Laustsen, C. (2017). Ex vivo hyperpolarized MR spectroscopy on isolated renal tubular cells: A novel technique for cell energy phenotyping.. Magnetic Resonance in Medicine, 78(2), 457-461
Open this publication in new window or tab >>Ex vivo hyperpolarized MR spectroscopy on isolated renal tubular cells: A novel technique for cell energy phenotyping.
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2017 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 78, no 2, p. 457-461Article in journal (Refereed) Published
Abstract [en]

PURPOSE: It has been demonstrated that hyperpolarized (13) C MR is a useful tool to study cultured cells. However, cells in culture can alter phenotype, which raises concerns regarding the in vivo significance of such findings. Here we investigate if metabolic phenotyping using hyperpolarized (13) C MR is suitable for cells isolated from kidney tissue, without prior cell culture.

METHODS: Isolation of tubular cells from freshly excised kidney tissue and treatment with either ouabain or antimycin A was investigated with hyperpolarized MR spectroscopy on a 9.4 Tesla preclinical imaging system.

RESULTS: Isolation of tubular cells from less than 2 g of kidney tissue generally resulted in more than 10 million live tubular cells. This amount of cells was enough to yield robust signals from the conversion of (13) C-pyruvate to lactate, bicarbonate and alanine, demonstrating that metabolic flux by means of both anaerobic and aerobic pathways can be quantified using this technique.

CONCLUSION: Ex vivo metabolic phenotyping using hyperpolarized (13) C MR in a preclinical system is a useful technique to study energy metabolism in freshly isolated renal tubular cells. This technique has the potential to advance our understanding of both normal cell physiology as well as pathological processes contributing to kidney disease.

Keywords
MRI, hyperpolarization, kidney, renal tubular cells, renal tubular metabolism
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-318081 (URN)10.1002/mrm.26379 (DOI)000405637000005 ()27529808 (PubMedID)
Funder
Swedish Research Council
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-01-13Bibliographically approved
Stridh, S., Palm, F., Takahashi, T., Ikegami-Kawai, M., Friederich, M. & Hansell, P. (2017). Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin. International Journal of Molecular Sciences, 18(12), Article ID 2701.
Open this publication in new window or tab >>Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin
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2017 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 12, article id 2701Article in journal (Refereed) Published
Abstract [en]

The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10−10 and 10−8 M) increased HA 3-fold. On the contrary, at a high concentration (10−6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling.

Keywords
hyaluronan, kidney, interstitium, medulla, endothelin, vasopressin, angiotensin II
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-340316 (URN)10.3390/ijms18122701 (DOI)000418896700203 ()
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved
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