| 1. |
- Persson, Patrik, et al.
(författare)
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Adenosine A(2)a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress
- 2015
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Ingår i: Acta Physiologica. - : Wiley: 12 months. - 1748-1708 .- 1748-1716. ; 214:3, s. 311-318
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Tidskriftsartikel (refereegranskat)abstract
- AimDiabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. This study investigates whether chronic stimulation of the adenosine A(2a) receptor (A(2a)AR) protects kidney function in insulinopenic diabetic rats. MethodsStreptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A(2a)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. ResultsGlomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A(2a)AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A(2a)AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A(2a)AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF- and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness. ConclusionChronic A(2a)AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.
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| 2. |
- Friederich, Malou, 1983-, et al.
(författare)
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Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes
- 2018
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Ingår i: Acta Physiologica. - : WILEY. - 1748-1708 .- 1748-1716. ; 223:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Persson, Patrik, et al.
(författare)
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Acute intrarenal angiotensin (1-7) infusion decreases diabetes-induced glomerular hyperfiltration but increases kidney oxygen consumption in the rat
- 2019
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Ingår i: Acta Physiologica. - : WILEY. - 1748-1708 .- 1748-1716. ; 226:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- 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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| 5. |
- Persson, Patrik, et al.
(författare)
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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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| 6. |
- 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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