| 1. |
- Friederich-Persson, Malou, et al.
(författare)
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Increased kidney metabolism as a pathway to kidney tissue hypoxia and damage : effects of triiodothyronine and dinitrophenol in normoglycemic rats.
- 2013
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer-Verlag New York. - 0065-2598 .- 2214-8019. - 9781461474111 - 9781461472568 ; 789, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.
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| 2. |
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| 3. |
- 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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| 4. |
- Sivertsson, Ebba, et al.
(författare)
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Dose-dependent regulation of kidney mitochondrial function by angiotensin II
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.
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| 5. |
- 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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| 6. |
- Luther, Tomas, et al.
(författare)
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Renal mitochondrial dysfunction in ovine experimental Sepsis Associated Acute Kidney Injury
- 2022
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Tidskriftsartikel (refereegranskat)abstract
- Sheep develop sepsis associated acute kidney injury (SA-AKI) during experimental sepsis despite normal to increased renal oxygen delivery (DO2). A disturbed relation between oxygen consumption (VO2) and renal sodium transport have been demonstrated in sheep and in clinical studies of AKI, which could be explained by mitochondrial dysfunction. We investigated the function of isolated renal mitochondria in comparison to renal oxygen handling in an ovine hyperdynamic model of SA-AKI. Anesthetized sheep were randomized to either an infusion of live Escherichia Coli with resuscitative measures (Sepsis group, n=13) or served as controls (n=8) for 28 hours. Renal VO2 and sodium transport were repeatedly measured. Live cortical mitochondria were isolated at baseline and end of experiment and assessed in vitro with high resolution respirometry. Sepsis markedly reduced creatinine clearance and the relation between sodium transport and renal VO2 was decreased in septic compared with control sheep. Cortical mitochondrial function was altered in septic sheep with reduced Respiratory Control Ratio (RCR) (6.0±1.5 vs. 8.2±1.6; p=0.006) and increased Complex II/Complex I-ratio (CII/CI) during State 3 (1.6±0.2 vs. 1.3±0.1; p=0.0014) mainly due to decreased Complex I-dependent State 3 respiration (p=0.016). However, no differences in renal mitochondrial efficiency or mitochondrial uncoupling were found. In conclusion, renal mitochondrial dysfunction comprised of a reduction of the RCR and an increased CII/CI-relation in State 3 was demonstrated in an ovine model of SA-AKI. However, the disturbed relation between renal VO2 and renal sodium transport could not be explained by a change in renal cortical mitochondrial efficiency or uncoupling.
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| 7. |
- Luther, Tomas, et al.
(författare)
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Renal mitochondrial dysfunction in ovine experimental sepsis-associated acute kidney injury
- 2023
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 324:6, s. 571-580
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Tidskriftsartikel (refereegranskat)abstract
- Sheep develop sepsis-associated acute kidney injury (SA-AKI) during experimental sepsis despite normal to increased renal oxygen delivery. A disturbed relation between oxygen consumption (V_ O2) and renal Na thorn transport has been demonstrated in sheep and in clinical studies of AKI, which could be explained by mitochondrial dysfunction. We investigated the function of isolated renal mitochondria compared with renal oxygen handling in an ovine hyperdynamic model of SA-AKI. Anesthetized sheep were randomized to either an infusion of live Escherichia coli with resuscitative measures (sepsis group; n = 13 animals) or served as controls (n = 8 animals) for 28 h. Renal V_ O2 and Na thorn transport were repeatedly measured. Live cortical mitochondria were isolated at baseline and at the end of the experiment and assessed in vitro with high-resolution respirometry. Sepsis markedly reduced creatinine clearance, and the relation between Na thorn transport and renal V_ O2 was decreased in septic sheep compared with control sheep. Cortical mitochondrial function was altered in septic sheep with a reduced respiratory control ratio (6.0 & PLUSMN; 1.5 vs. 8.2 & PLUSMN; 1.6, P = 0.006) and increased complex II-to-complex I ratio during state 3 (1.6 & PLUSMN; 0.2 vs. 1.3 & PLUSMN; 0.1, P = 0.0014) mainly due to decreased complex I-dependent state 3 respiration (P = 0.016). However, no differences in renal mitochondrial efficiency or mitochondrial uncoupling were found. In conclusion, renal mitochondrial dysfunction composed of a reduction of the respiratory control ratio and an increased complex II/complex I relation in state 3 was demonstrated in an ovine model of SA-AKI. However, the disturbed relation between renal V_ O2 and renal Na thorn transport could not be explained by a change in renal cortical mitochondrial efficiency or uncoupling.NEW & NOTEWORTHY We studied the function of renal cortical mitochondria in relation to oxygen consumption in an ovine model of sepsis with acute kidney injury. We demonstrated changes in the electron transport chain induced by sepsis consisting of a reduced respiratory control ratio mainly by a reduced complex I-mediated respiration. Neither an increase in mitochondrial uncoupling nor a reduction in mitochondrial efficiency was demonstrated and cannot explain why oxygen consumption was unaffected despite reduced tubular transport.
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| 8. |
- Patinha, Daniela, et al.
(författare)
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Determinants of renal oxygen metabolism during low Na+ diet : effect of angiotensin II AT1 and aldosterone receptor blockade
- 2020
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Ingår i: Journal of Physiology. - 0022-3751 .- 1469-7793. ; 598:23, s. 5573-5587
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Tidskriftsartikel (refereegranskat)abstract
- Reducing Na(+)intake reduces the partial pressure of oxygen in the renal cortex and activates the renin-angiotensin-aldosterone system. In the absence of high blood pressure, these consequences of dietary Na(+)reduction may be detrimental for the kidney. In a normotensive animal experimental model, reducing Na(+)intake for 2 weeks increased renal oxygen consumption, which was normalized by mineralocorticoid receptor blockade. Furthermore, blockade of the angiotensin II AT(1)receptor restored cortical partial pressure of oxygen by improving oxygen delivery. This shows that increased activity of the renin-angiotensin-aldosterone system contributes to increased oxygen metabolism in the kidney after 2 weeks of a low Na(+)diet. The results provide insights into dietary Na(+)restriction in the absence of high blood pressure, and its consequences for the kidney. Reduced Na(+)intake reduces thePO2(partial pressure of oxygen) in the renal cortex. Upon reduced Na(+)intake, reabsorption along the nephron is adjusted with activation of the renin-angiotensin-aldosterone system (RAAS). Thus, we studied the effect of reduced Na(+)intake on renal oxygen homeostasis and function in rats, and the impact of intrarenal angiotensin II AT(1)receptor blockade using candesartan and mineralocorticoid receptor blockade using canrenoic acid potassium salt (CAP). Male Sprague-Dawley rats were fed standard rat chow containing normal (0.25%) and low (0.025%) Na(+)for 2 weeks. The animals were anaesthetized (thiobutabarbital 120 mg kg(-1)) and surgically prepared for kidney oxygen metabolism and function studies before and after acute intrarenal arterial infusion of candesartan (4.2 mu g kg(-1)) or intravenous infusion of CAP (20 mg kg(-1)). Baseline mean arterial pressure and renal blood flow were similar in both dietary groups. Fractional Na(+)excretion and cortical oxygen tension were lower and renal oxygen consumption was higher in low Na(+)groups. Neither candesartan nor CAP affected arterial pressure. Renal blood flow and cortical oxygen tension increased in both groups after candesartan in the low Na(+)group. Fractional Na(+)excretion was increased and oxygen consumption reduced in the low Na(+)group after CAP. These results suggest that blockade of angiotensin II AT(1)receptors has a major impact upon oxygen delivery during normal and low Na(+)conditions, while aldosterone receptors mainly affect oxygen metabolism following 2 weeks of a low Na(+)diet.
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| 9. |
- 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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| 10. |
- Persson, Patrik, et al.
(författare)
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Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes
- 2013
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer-Verlag New York. - 0065-2598 .- 2214-8019. - 9781461447719 ; 765, s. 225-230
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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