| 1. |
- Laustsen, Christoffer, et al.
(författare)
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Antioxidant treatment attenuates lactate production in diabetic nephropathy
- 2017
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 312:1, s. F192-F199
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Sivertsson, Ebba, et al.
(författare)
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Lowering plasma levels of protein-bound uremic toxins improves cardiac output and renal oxygenation in a rat model of chronic kidney disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Chronic kidney disease (CKD) is an increasing health problem which is closely associated with cardiac dysfunction. In CKD uremic toxins accumulate as kidney function declines. Indoxyl sulfate is a uremic toxin that induces kidney tissue hypoxia, proteinuria and kidney damage. Furthermore, high salt intake is a growing health issue worldwide. In this study, we investigated the effect of reducing plasma indoxyl sulfate in a rat model of CKD challenged with high salt intake and compared the effects to that of conventional treatment using an angiotensin converting enzyme inhibitor (ACEI). In rats, the right kidney and 2/3 of the left kidney were surgically removed (5/6 nephrectomy). Animals were fed a normal salt containing diet for four weeks and randomized to either vehicle or chronic treatment with either the oral absorbent AST-120 or the ACEI enalapril. Thereafter, kidney function was measured before and after a week of high salt intake. Cardiac output was measured at the end of the study period. A reduction of plasma levels of indoxyl sulfate by AST-120 improved cardiac output as well as urinary oxidative stress and proteinuria. ACEI reduced oxidative stress in kidney tissue and significantly improved proteinuria and the glomerular filtration rate in response to the high salt intake. Both interventions improved intrarenal oxygen availability.In conclusion, decreasing circulating levels of protein bound uremic toxins, e.g. indoxyl sulfate, improves cardiac output, reduces urinary oxidative stress and proteinuria in experimental CKD. Reduced angiotensin II signaling has direct reno-protective effects by decreasing intrarenal oxidative stress, protecting renal reserve and increasing urinary Na+ excretion during high salt intake. Both treatments had striking effects on cortical oxygen availability. A dual strategy, to reduce indoxyl sulfate and angiotensin II signaling simultaneously, could be an efficient strategy to target both cardiac and renal dysfunction in CKD, to further slow progression of disease.
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| 3. |
- Sivertsson, Ebba, 1984-
(författare)
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Oxygen Metabolism in Experimental Kidney Disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tubulointerstitial hypoxia has been proposed a unifying mechanism behind the development of chronic kidney disease (CKD), regardless of primary diagnosis. Important factors that contribute to the development of hypoxia are reduced bioavailability of nitric oxide (NO), oxidative stress and mitochondria uncoupling. Diabetes and hypertension are the leading causes of CKD. Once established, CKD is a progressive disease and there is no curative treatment. This thesis aimed to investigate the in vivo kidney oxygen metabolism and in vitro mitochondria function in animal models of pathological conditions known to cause kidney injury.The immunosuppressant drug rapamycin has been suggested to counteract diabetic nephropathy by reducing kidney hypertrophy and proteinuria. In a rat model of diabetes type 1, we demonstrate that rapamycin induced intrarenal hypoxia, oxidative stress and mitochondria leak respiration. In diabetic animals, these changes, together with diabetes induced tubular injury, were further aggravated by rapamycin. Proteinuria was decreased by rapamycin in diabetic animals, due to altered glomerular permeability of large molecules. When investigating the role of hypoxia in development of nephropathy there are often confounding factors such as concomitant hyperglycemia, hypertension and oxidative stress to consider. In rats, we demonstrate that increased kidney metabolism, induced by increased thyroid hormone signaling, induced kidney hypoxia, proteinuria and mitochondria leak respiration. Importantly blood glucose, blood pressure and oxidative stress was unchanged. This provides further evidence that hypoxia per se can induce kidney injury. The role of mitochondria dysfunction in hypertensive kidney disease is unclear and angiotensin II (Ang II) has been shown to inhibit mitochondria respiration. In a mouse model of hypertension, we demonstrate that Ang II regulation of mitochondria respiration was dose-dependent. Low Ang II signaling increased leak respiration without compromising efficiency of oxidative phosphorylation. In contrast, high Ang II signaling inhibited mitochondria respiration and decreased efficiency of oxidative phosphorylation. Finally, uremic toxins accumulate in patients with CKD and correlate with the degree of decline in kidney function. In a rat model of CKD, we demonstrate that treatment to reduce plasma levels of protein bound uremic toxins improves cardiac output and kidney oxygenation. In summary, the common denominator for pathological conditions investigated in this thesis is the occurrence of intrarenal hypoxia. This thesis demonstrates that increased mitochondria oxygen consumption via leak respiration as an important contributing factor. Further, targeting plasma levels of circulating uremic toxins may be a potential treatment strategy to slow the rate of progression of CKD.
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| 4. |
- Sivertsson, Ebba, 1984-, et al.
(författare)
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Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The proposed mechanisms for the development of nephropathy are many, complex and often overlapping. Although recent literature strongly supports a role of kidney hypoxia as an independent pathway to nephropathy, the evidence remains inconclusive since the role of hypoxia is difficult to differentiate from confounding factors such as hyperglycemia, hypertension and oxidative stress. By increasing kidney oxygen consumption using triiodothyronine (T3) and, thus, avoiding these confounding factors, the aim of the present study was to investigate renal hypoxia per se as a causal pathway for the development of nephropathy.Healthy Sprague-Dawley rats were treated with T3 (10 µg/kg/day) and the angiotensin II AT1-receptor antagonist candesartan (1 mg/kg in drinking water) to eliminate effects of T3-induced renin release for 7 weeks after which in vivo kidney function, oxygen metabolism and mitochondrial function were evaluated.T3 did not affect glomerular filtration rate or renal blood flow, but increased total kidney oxygen consumption resulting in cortical hypoxia. Nephropathy, demonstrated as proteinuria and albuminuria developed in T3-treated animals. Mitochondria uncoupling mediated by uncoupling protein 2 and the adenosine nucleotide transporter was demonstrated as a mechanism causing the increased kidney oxygen consumption. Importantly, blood glucose levels, mean arterial blood pressure and oxidative stress levels were not affected by T3. In conclusion, the present study provides further evidence for increased kidney oxygen consumption causing intrarenal tissue hypoxia, as a causal pathway for development of nephropathy.
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| 5. |
- Burmakin, Mikhail, et al.
(författare)
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Pharmacological HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation
- 2021
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Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 233:1
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Hypoxia-inducible factors (HIFs) are O2 -sensitive transcription factors that regulate multiple biological processes which are essential for cellular adaptation to hypoxia. Small molecule inhibitors of HIF-prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-dependent transcriptional programs and have broad clinical potential. HIF-PHIs are currently in global late-stage clinical development for the treatment of anaemia associated with chronic kidney disease. Although the effects of hypoxia on renal haemodynamics and function have been studied in animal models and in humans living at high altitude, the effects of pharmacological HIF activation on renal haemodynamics, O2 metabolism and metabolic efficiency are not well understood.METHODS: Using a cross-sectional study design, we investigated renal haemodynamics, O2 metabolism, gene expression and NO production in healthy rats treated with different doses of HIF-PHIs roxadustat or molidustat compared to vehicle control.RESULTS: Systemic administration of roxadustat or molidustat resulted in a dose-dependent reduction in renovascular resistance (RVR). This was associated with increased glomerular filtration rate (GFR), urine flow and tubular sodium transport rate (TNa ). Although both total O2 delivery and TNa were increased, more O2 was extracted per transported sodium in rats treated with high-doses of HIF-PHIs, suggesting a reduction in metabolic efficiency. Changes in RVR and GFR were associated with increased nitric oxide (NO) generation and substantially suppressed by pharmacological inhibition of NO synthesis.CONCLUSIONS: Our data provide mechanistic insights into dose-dependent effects of short-term pharmacological HIF activation on renal haemodynamics, glomerular filtration and O2 metabolism and identify NO as a major mediator of these effects.
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| 6. |
- Christensen, Michael, et al.
(författare)
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Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-2
- 2019
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Ingår i: Diabetes/Metabolism Research Reviews. - : WILEY. - 1520-7552 .- 1520-7560. ; 35:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.Methods: Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance.Results: Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.Conclusions: Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.
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| 7. |
- Eckerbom, Per, 1974-, et al.
(författare)
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Circadian variation in renal blood flow and kidney function in healthy volunteers monitored with noninvasive magnetic resonance imaging
- 2020
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 319:6, s. F966-F978
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Tidskriftsartikel (refereegranskat)abstract
- Circadian regulation of kidney function is involved in maintaining whole body homeostasis, and dysfunctional circadian rhythm can potentially be involved in disease development. Magnetic resonance imaging (MRI) provides reliable and reproducible repetitive estimates of kidney function noninvasively without the risk of adverse events associated with contrast agents and ionizing radiation. The purpose of this study was to estimate circadian variations in kidney function in healthy human subjects with MRI and to relate the findings to urinary excretions of electrolytes and markers of kidney function. Phase-contrast imaging, arterial spin labeling, and blood oxygen level-dependent transverse relaxation rate (R2*) mapping were used to assess total renal blood flow and regional perfusion as well as intrarenal oxygenation in eight female and eight male healthy volunteers every fourth hour during a 24-h period. Parallel with MRI scans, standard urinary and plasma parameters were quantified. Significant circadian variations of total renal blood flow were found over 24 h, with increasing flow from noon to midnight and decreasing flow during the night. In contrast, no circadian variation in intrarenal oxygenation was detected. Urinary excretions of electrolytes, osmotically active particles, creatinine, and urea all displayed circadian variations, peaking during the afternoon and evening hours. In conclusion, total renal blood flow and kidney function, as estimated from excretion of electrolytes and waste products, display profound circadian variations, whereas intrarenal oxygenation displays significantly less circadian variation.
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| 8. |
- Edwards, Aurelie, et al.
(författare)
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A model of mitochondrial O-2 consumption and ATP generation in rat proximal tubule cells
- 2020
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Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 318:1, s. F248-F259
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Tidskriftsartikel (refereegranskat)abstract
- Oxygen tension in the kidney is mostly determined by O-2 consumption (Qo(2)), which is, in turn, closely linked to tubular Na+ reabsorption. The objective of the present study was to develop a model of mitochondrial function in the proximal tubule (PT) cells of the rat renal cortex to gain more insight into the coupling between Qo(2), ATP formation (G(ATP)), ATP hydrolysis (QATP), and Na+ transport in the PH. The present model correctly predicts in vitro and in vivo measurements of Qo(2), Owns, and ATP and P-i concentrations in PT cells. Our simulations suggest that O-2 levels are not rate limiting in the proximal convoluted tubule, absent large metabolic perturbations. The model predicts that the rate of ATP hydrolysis and cytoplasmic pH each substantially regulate the G AT p-to-Qo(2) ratio, a key determinant of the number of Na+ moles actively reabsorbed per mole of O-2 consumed. An isolated increase in QATP or in cytoplasmic pH raises the GAS-to-Qo(2) ratio. Thus. variations in Na+ reabsorption and pH along the PT may, per se, generate axial heterogeneities in the efficiency of mitochondria' metabolism and Na+ transport. Our results also indicate that the G(AT)(P)-to-Qo(2) ratio is strongly impacted not only by H+ leak permeability. which reflects mitochondrial uncoupling, but also by K+ leak pathways. Simulations suggest that the negative impact of increased uncoupling in the diabetic kidney on mitochondrial metabolic efficiency is partly counterbalanced by increased rates of Na+ transport and ATP consumption. This model provides a framework to investigate the role of mitochondrial dysfunction in acute and chronic renal diseases.
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| 9. |
- Franzén, Stephanie, et al.
(författare)
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Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats
- 2018
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Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 314:3, s. F439-F444
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- 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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