| 431. |
- Persson, Patrik
(författare)
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Aspects of Regulation of GFR and Tubular Function in the Diabetic Kidney : Roles of Adenosine, Nitric Oxide and Oxidative Stress
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetic nephropathy is the main cause for initiation of renal replacement therapy and early symptoms in patients include increased glomerular filtration rate (GFR), decreased oxygen tension and albuminuria, followed by a progressive decline in GFR and loss of kidney function. Experimental models of diabetes display increased GFR, decreased tissue oxygenation and nitric oxide bioavailability. These findings are likely to be intertwined in a mechanistic pathway to kidney damage and this thesis investigated their roles in the development of diabetic nephropathy. In vivo, diabetes-induced oxidative stress stimulates renal tubular Na+ transport and in vitro, proximal tubular cells from diabetic rats display increased transport-dependent oxygen consumption, demonstrating mechanisms contributing to decreased kidney oxygenation. In control animals, endogenous adenosine reduces vascular resistance of the efferent arteriole via adenosine A2-receptors resulting in reduced filtration fraction. However, in diabetes, adenosine A2-signalling is dysfunctional resulting in increased GFR via increased filtration fraction. This is caused by reduced adenosine A2a receptor-mediated vasodilation of efferent arterioles. The lack of adenosine-signaling in diabetes is likely due to reduced local adenosine concentration since adenosine A2a receptor activation reduced GFR only in diabetic animals by efferent arteriolar vasodilation. Furthermore, sub-optimal insulin treatment also alleviates increased filtration pressure in diabetes. However, this does not affect GFR due to a simultaneously induction of renal-blood flow dependent regulation of GFR by increasing the filtration coefficient. In diabetes, there is decreased bioavailability of nitric oxide, resulting in alterations that may contribute to diabetes-induced hyperfiltration and decreased oxygenation. Interestingly, increased plasma concentration of l-arginine, the substrate for nitric oxide production, prevents the development of increased GFR and proteinuria, but not increased oxygen consumption leading to sustained intra-renal hypoxia in diabetes. This thesis concludes that antioxidant treatment directed towards the NADPH oxidase as well maneuvers to promote nitric oxide production is beneficial in diabetic kidneys but is targeting different pathways i.e. transport-dependent oxygen consumption in the proximal tubule by NADPH oxidase inhibition and intra-renal hemodynamics after increased plasma l-arginine. Also, the involvement and importance of efferent arteriolar resistance in the development of diabetes-induced hyperfiltration via reduced adenosine A2a signaling is highlighted.
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| 432. |
- Persson, Patrik, et al.
(författare)
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Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity
- 2017
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 312:2, s. F278-F283
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 433. |
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| 434. |
- Persson, Per, et al.
(författare)
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GeoNotes: social enhancement of physical space
- 2001. - 1
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Ingår i: Proceeding CHI EA '01 CHI '01 Extended Abstracts on Human Factors in Computing Systems. - Seattle, Washington, USA : ACM Publications.
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Konferensbidrag (refereegranskat)abstract
- The GeoNotes system allows users to annotate physical locations with virtual 'notes', which are then pushed to or accessed by other users when in the vicinity. GeoNotes employs a number of social filtering techniques, which all rely on logging of usage rather than content.
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| 435. |
- Persson, Per, et al.
(författare)
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GeoNotes: social enhancement of physical space
- 2001. - 1
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Ingår i: ERCIM News. ; :47
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Positioning technology is often associated with locating people in geographical space. The GeoNotes system, however, positions pieces of information. GeoNotes allows all users to annotate physical locations with virtual "notes", which are then pushed to or accessed by other users when in the vicinity.
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| 436. |
- Persson, Patrik, et al.
(författare)
-
Hypoxia-inducible factor activation in diabetic kidney disease.
- 2017
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Ingår i: Current opinion in nephrology and hypertension. - 1062-4821 .- 1473-6543. ; 26:5, s. 345-350
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 437. |
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| 438. |
- Persson, Patrik, et al.
(författare)
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L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat
- 2014
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Ingår i: Hypertension. - : Lippincott Williams & Wilkins. - 0194-911X .- 1524-4563. ; 64:2, s. 323-329
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 439. |
- Persson, Patrik, et al.
(författare)
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NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes
- 2012
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Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 302:12, s. R1443-R1449
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Tidskriftsartikel (refereegranskat)abstract
- Sustained hyperglycemia is associated with increased oxidative stress resulting in decreased intrarenal oxygen tension (Po-2) due to increased oxygen consumption (Qo(2)). Chronic blockade of the main superoxide radicals producing system, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, normalizes Qo(2) by isolated proximal tubular cells (PTC) and reduces proteinuria in diabetes. The aim was to investigate the effects of acute NADPH oxidase inhibition on tubular Na+ transport and kidney Po-2 in vivo. Glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), Na+ excretion, fractional Li+ excretion, and intrarenal Po-2 was measured in control and streptozotocin-diabetic rats during baseline and after acute NADPH oxidase inhibition using apocynin. The effects on tubular transporters were investigated using freshly isolated PTC. GFR was increased in diabetics compared with controls (2.2 +/- 0.3 vs. 1.4 +/- 0.1 ml.min (-1).kidney (-1)). RBF was similar in both groups, resulting in increased FF in diabetics. Po-2 was reduced in cortex and medulla in diabetic kidneys compared with controls (34.4 +/- 0.7 vs. 42.5 +/- 1.2 mmHg and 15.7 +/- 1.2 vs. 25.5 +/- 2.3 mmHg, respectively). Na+ excretion was increased in diabetics compared with controls (24.0 +/- 4.7 vs. 9.0 +/- 2.0 mu m.min(-1).kidney(-1)). In controls, all parameters were unaffected. However, apocynin increased Na+ excretion (+112%) and decreased fractional lithium reabsorption (-10%) in diabetics, resulting in improved cortical (+14%) and medullary (+28%) Po-2. Qo(2) was higher in PTC isolated from diabetic rats compared with control. Apocynin, dimethylamiloride, and ouabain reduced Qo(2), but the effects of combining apocynin with either dimethylamiloride or ouabain were not additive. In conclusion, NADPH oxidase inhibition reduces tubular Na+ transport and improves intrarenal Po-2 in diabetes.
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| 440. |
- Persson, Patrik, et al.
(författare)
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Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration
- 2015
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 87:1, s. 109-115
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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