| 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. |
- Nordquist, Lina, et al.
(författare)
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Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy
- 2015
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Ingår i: Journal of the American Society of Nephrology. - : American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 26:2, s. 328-338
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Tidskriftsartikel (refereegranskat)abstract
- Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glonnerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharnnacologic activation of the HIF system may prevent development of diabetic nephropathy.
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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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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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| 6. |
- Sivertsson, Ebba, et al.
(författare)
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Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability
- 2018
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Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 314:5, s. F864-F872
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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