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Persson, Patrik
Publications (10 of 16) Show all publications
Persson, P., Fasching, A. & Palm, F. (2019). Acute intrarenal angiotensin (1-7) infusion decreases diabetes-induced glomerular hyperfiltration but increases kidney oxygen consumption in the rat. Acta Physiologica, 226(1), Article ID e13254.
Open this publication in new window or tab >>Acute intrarenal angiotensin (1-7) infusion decreases diabetes-induced glomerular hyperfiltration but increases kidney oxygen consumption in the rat
2019 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 226, no 1, article id e13254Article in journal (Refereed) Published
Abstract [en]

Aim: Common kidney alterations early after the onset of insulinopenic diabetes include glomerular hyperfiltration, increased oxygen consumption and tissue hypoxia. Increased activity of the renin-angiotensin-aldosterone system (RAAS) has been implicated in most of these early alterations. The RAAS peptide angiotensin (1-7) has the potential to modulate RAAS-mediated alterations in kidney function. Thus, the aim of the present study was to determine the acute effects of angiotensin (1-7) in the kidney of insulinopenic type 1 diabetic rat and the results compared to that of normoglycaemic controls.

Methods: Renal haemodynamics and oxygen homeostasis were measured 3 weeks after administration of streptozotocin before and after acute intrarenal infusion of angiotensin (1-7) at a dose of 400 ng min(-1).

Results: Arterial pressure and renal blood flow were similar between groups and not affected by exogenous angiotensin (1-7). Diabetics presented with glomerular hyperfiltration, increased urinary sodium excretion and elevated kidney oxygen consumption. Angiotensin (1-7) infusion normalized glomerular filtration, increased urinary sodium excretion, decreased proximal tubular reabsorption, and elevated kidney oxygen consumption even further. The latter resulting in tubular electrolyte transport inefficiency. Angiotensin (1-7) did not affect tissue oxygen tension and had no significant effects in controls on any of the measured parameters.

Conclusion: Diabetes results in increased responsiveness to elevated levels of angiotensin (1-7) which is manifested as inhibition of tubular sodium transport and normalization of glomerular filtration. Furthermore, elevated angiotensin (1-7) levels increase kidney oxygen consumption in the diabetic kidney even further which affects tubular electrolyte transport efficiency negatively.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
diabetes, filtration fraction, glomerular filtration rate, lithium clearance, renal blood flow, sodium excretion, streptozotocin
National Category
Physiology Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-383158 (URN)10.1111/apha.13254 (DOI)000465102700010 ()30635985 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Heart Lung FoundationErnfors FoundationSwedish Society for Medical Research (SSMF)
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically 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
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
Persson, P. & Palm, F. (2017). Hypoxia-inducible factor activation in diabetic kidney disease.. Current opinion in nephrology and hypertension, 26(5), 345-350
Open this publication in new window or tab >>Hypoxia-inducible factor activation in diabetic kidney disease.
2017 (English)In: Current opinion in nephrology and hypertension, ISSN 1062-4821, E-ISSN 1473-6543, Vol. 26, no 5, p. 345-350Article, review/survey (Refereed) Published
Abstract [en]

PURPOSE OF REVIEW:

Tissue hypoxia is present in kidneys from diabetic patients and constitutes a central pathway to diabetic kidney disease (DKD). This review summarizes regulation of hypoxia inducible factor (HIF) and interventions towards the same for treatment of DKD.

RECENT FINDINGS:

In the hypoxic diabetic kidney, HIF activity and the effects of HIF signaling seem to be cell-specific. In mesangial cells, elevated glucose levels induce HIF activity by a hypoxia-independent mechanism. Elevated HIF activity in glomerular cells promotes glomerulosclerosis and albuminuria, and inhibition of HIF protects glomerular integrity. However, tubular HIF activity is suppressed and HIF activation protects mitochondrial function and prevents development of diabetes-induced tissue hypoxia, tubulointerstitial fibrosis and proteinuria. No clinical treatment targeting kidney hypoxia is currently available, but development of prolyl hydroxylase inhibitors to promote HIF activity to treat renal anemia could potentially also target diabetes-induced kidney hypoxia.

SUMMARY:

Increasing HIF activity in the diabetic kidney may possess a novel target for treatment of DKD by improving kidney oxygen homeostasis. However, HIF-mediated glomerulosclerosis may be a concern. The kidney outcomes from the ongoing clinical trials using prolyl hydroxylase inhibitors may provide additional insights into the complex role of HIF signaling in the diabetic kidney.

Keywords
diabetes, hypoxia inducible factor-1 a, hypoxia inducible factor-1 b, nephropathy, prolyl-hydroxylase
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-322784 (URN)10.1097/MNH.0000000000000341 (DOI)000407060000003 ()
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Society for Medical Research (SSMF)
Available from: 2017-05-30 Created: 2017-05-30 Last updated: 2018-02-22Bibliographically approved
Persson, P., Friederich-Persson, M., Fasching, A., Hansell, P., Inagi, R. & Palm, F. (2015). Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress. Acta Physiologica, 214(3), 311-318
Open this publication in new window or tab >>Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress
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2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 3, p. 311-318Article in journal (Refereed) Published
Abstract [en]

AIM: Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. The present study investigates if chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats.

METHODS: Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers.

RESULTS: Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF-α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness.

CONCLUSION: Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-252416 (URN)10.1111/apha.12511 (DOI)000356306300007 ()25891445 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilÅke Wiberg FoundationSwedish Diabetes Association
Available from: 2015-05-06 Created: 2015-05-06 Last updated: 2018-01-11Bibliographically approved
Persson, P., Hansell, P. & Palm, F. (2015). Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration. Kidney International, 87(1), 109-115
Open this publication in new window or tab >>Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration
2015 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 87, no 1, p. 109-115Article in journal (Refereed) Published
Abstract [en]

Diabetes is associated with increased risk for development of kidney disease, and an increased glomerular filtration rate is an early indication of altered kidney function. Here we determine whether reduced adenosine A2a receptor-mediated vasodilation of the efferent arteriole contributes to the increased glomerular filtration rate in diabetes. The glomerular filtration rate, renal blood flow, and proximal tubular stop flow pressure were investigated in control and streptozotocin-diabetic rats during baseline and after administration of the adenosine A2a receptor antagonist ZM241385 or the adenosine A2a receptor agonist CGS21680. The diabetes-induced glomerular hyperfiltration was reduced by 24% following A2a receptor stimulation but was unaffected by A2a receptor inhibition. Contrarily, glomerular filtration rate in controls increased by 22% after A2a receptor inhibition and was unaffected by A2a stimulation. The increased glomerular filtration rate after A2a receptor inhibition in controls and decreased glomerular filtration rate after A2a receptor activation in diabetics were caused by increased and decreased stop flow pressure, respectively. None of the interventions affected renal blood flow. Thus, the normal adenosine A2a receptor-mediated tonic vasodilation of efferent arterioles is abolished in the diabetic kidney. This causes increased efferent arteriolar resistance resulting in increased filtration fraction and hyperfiltration.

Keywords
kidney, CGS21680, renal blood flow, glomerular filtration rate, net filtration pressure
National Category
Physiology
Research subject
Physiology; Medical Science
Identifiers
urn:nbn:se:uu:diva-195428 (URN)10.1038/ki.2014.219 (DOI)000346977900014 ()
Funder
Swedish Research Council
Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2018-01-11Bibliographically approved
Persson, P., Fasching, A., Teerlink, T., Hansell, P. & Palm, F. (2014). L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat. Hypertension, 64(2), 323-329
Open this publication in new window or tab >>L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat
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2014 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 2, p. 323-329Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus–induced oxidative stress causes increased renal oxygen consumption and intrarenal tissue hypoxia. Nitric oxide is an important determinant of renal oxygen consumption and electrolyte transport efficiency. The present study investigates whether l-arginine or l-citrulline to promote nitric oxide production prevents the diabetes mellitus–induced kidney dysfunction. Glomerular filtration rate, renal blood flow, in vivo oxygen consumption, tissue oxygen tension, and proteinuria were investigated in control and streptozotocin-diabetic rats with and without chronic l-arginine or l-citrulline treatment for 3 weeks. Untreated and l-arginine–treated diabetic rats displayed increased glomerular filtration rate (2600±162 versus 1599±127 and 2290±171 versus 1739±138 µL/min per kidney), whereas l-citrulline prevented the increase (1227±126 versus 1375±88 µL/min per kidney). Filtration fraction was increased in untreated diabetic rats because of the increase in glomerular filtration rate but not in l-arginine– or l-citrulline–treated diabetic rats. Urinary protein excretion was increased in untreated and l-arginine–treated diabetic rats (142±25 versus 75±7 and 128±7 versus 89±7 µg/min per kidney) but not in diabetic rats administered l-citrulline (67±7 versus 61±5 µg/min per kidney). The diabetes mellitus–induced tissue hypoxia, because of elevated oxygen consumption, was unaltered by any of the treatments. l-citrulline administered to diabetic rats increases plasma l-arginine concentration, which prevents the diabetes mellitus–induced glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a vascular effect.

National Category
Physiology Basic Medicine
Research subject
Medical Science; Physiology
Identifiers
urn:nbn:se:uu:diva-195487 (URN)10.1161/HYPERTENSIONAHA.114.03519 (DOI)000339120700023 ()24866144 (PubMedID)
Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2018-01-11Bibliographically approved
Persson, P., Fasching, A., Teerlink, T., Hansell, P. & Palm, F. (2014). L-citrulline, but not L-arginine, prevents diabetes-induced glomerular hyperfiltration and proteinuria. Paper presented at Experimental Biology Meeting, APR 26-30, 2014, San Diego, CA. The FASEB Journal, 28(1), Article ID 689.12.
Open this publication in new window or tab >>L-citrulline, but not L-arginine, prevents diabetes-induced glomerular hyperfiltration and proteinuria
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2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 689.12Article in journal, Meeting abstract (Other academic) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-246841 (URN)000346646703208 ()
Conference
Experimental Biology Meeting, APR 26-30, 2014, San Diego, CA
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2017-12-04Bibliographically approved
Friederich-Persson, M., Persson, P., Fasching, A., Hansell, P., Nangaku, M. & Palm, F. (2014). Renal hypoxia due to increased oxygen metabolism is an independent pathway to nephropathy. Paper presented at EXPERIMENTAL BIOLOGY 2014 - Transforming the Future through Science, EB, April 26-30, 2014, Sand Diego, USA. The FASEB Journal, 28(1), Article ID 890.6.
Open this publication in new window or tab >>Renal hypoxia due to increased oxygen metabolism is an independent pathway to nephropathy
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2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 890.6Article in journal, Meeting abstract (Other academic) Published
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-246750 (URN)000346651003217 ()
Conference
EXPERIMENTAL BIOLOGY 2014 - Transforming the Future through Science, EB, April 26-30, 2014, Sand Diego, USA
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2017-12-04Bibliographically approved
Persson, P., Hansell, P. & Palm, F. (2013). Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes. Advances in Experimental Medicine and Biology, 765, 225-230
Open this publication in new window or tab >>Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes
2013 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 225-230Article in journal (Refereed) Published
Abstract [en]

Alterations in glomerular filtration rate (GFR) are one of the earliest indications of altered kidney function in diabetes. Adenosine regulates GFR through tubuloglomerular feedback mechanism acting on adenosine A1 receptor. In addition, adenosine can directly regulate vascular tone by acting on A1 and A2 receptors expressed in afferent and efferent arterioles. Opposite to A1 receptors, A2 receptors mediate vasorelaxation. This study investigates the involvement of adenosine A2 receptors in regulation of renal blood flow (RBF) and GFR in control and diabetic kidneys. GFR was measured by inulin clearance and RBF by a transonic flow probe placed around the renal artery. Measurements were performed in isoflurane-anesthetized normoglycemic and alloxan-diabetic C57BL/6 mice during baseline and after acute administration of 3,7-dimethyl-1-propargylxanthine (DMPX), a selective A2 receptor antagonist. GFR and RBF were lower in diabetic mice compared to control (258 ± 61 vs. 443 ± 33 μl min -1 and 1,083 ± 51 vs. 1,405 ± 78 μl min -1). In control animals, DMPX decreased RBF by-6%, whereas GFR increased +44%. DMPX had no effects on GFR and RBF in diabetic mice. Sodium excretion increased in diabetic mice after A2 receptor blockade (+78%). In conclusion, adenosine acting on A2 receptors mediates an efferent arteriolar dilatation which reduces filtration fraction (FF) and maintains GFR within normal range in normoglycemic mice. However, this regulation is absent in diabetic mice, which may contribute to reduced oxygen availability in the diabetic kidney.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2013
Keywords
Alloxan, C57BL/6, DMPX, Renal blood flow
National Category
Medical and Health Sciences Basic Medicine
Identifiers
urn:nbn:se:uu:diva-186810 (URN)10.1007/978-1-4614-4989-8_31 (DOI)000339280100032 ()9781461447719 (ISBN)
Available from: 2012-12-12 Created: 2012-11-29 Last updated: 2018-01-12
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