The roles of NADPH‐oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney

Edlund, Jenny; Fasching, Angelica; Liss, Per; Hansell, Peter; Palm, Fredrik

doi:10.1002/dmrr.1099

Cited by 31 publications

(22 citation statements)

References 24 publications

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“…NAD(P)H oxidase expression is upregulated in the glomerulus and distal tubules of DN animals (12,44). Direct or indirect NADPH oxidase inhibition prevented the diabetes-induced oxidative stress in the kidney (2,4,11,14,27,44). Our results revealed that a NMNAT-containing protein such as Wld S may also retard diabetic renal injury development by increasing the NAD ϩ /NADH ratio and inhibiting the increase in NADPH oxidase activity.…”

Section: Discussionmentioning

confidence: 58%

Wld^Sameliorates renal injury in a type 1 diabetic mouse model

Zhu

Yang

Jin

et al. 2014

American Journal of Physiology-Renal Physiology

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S ameliorates renal injury in a type 1 diabetic mouse model. Am J Physiol Renal Physiol 306: F1348 -F1356, 2014. First published March 5, 2014 doi:10.1152/ajprenal.00418.2013 is the leading cause of end-stage kidney disease worldwide. The purpose of this study is to investigate whether the Wld S (slow Wallerian degeneration; also known as Wld) gene plays a renoprotective role during the progression of DN. Diabetes was induced in 8-wk-old male wild-type (WT) and C57BL/Wld S mice by streptozotocin (STZ) injection. Blood and urinary variables including blood glucose, glycated hemoglobin (GHb), insulin, urea nitrogen, and albumin/creatinine ratio were assessed 4, 7, and 14 wk after STZ injection. Periodic acid-Schiff staining, Masson staining, and silver staining were performed for renal pathological analyses. In addition, the renal ultrastructure was observed by electron microscope. The activities of p38 and ERK signaling in renal cortical tissues were evaluated by Western blotting. NAD ϩ /NADH ratio and NADPH oxidase activity were also measured. Moreover, the expressions of TNF-␣, IL-1, and IL-6 were examined. We provide experimental evidence demonstrating that the Wld S gene is expressed in kidney cells and protects against the early stage of diabetes-induced renal dysfunction and extracellular matrix accumulation through delaying the reduction of the NAD ϩ /NADH ratio, inhibiting the activation of p38 and ERK signaling, and suppressing oxidative stress as evidenced by the decreased NADPH oxidase activity and lower expression of TNF-␣, IL-1, and IL-6. Wld S

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Section: Discussionmentioning

confidence: 58%

Wld^Sameliorates renal injury in a type 1 diabetic mouse model

Zhu

Yang

Jin

et al. 2014

American Journal of Physiology-Renal Physiology

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“…Indicators of the production and/or bioavailability of reactive oxygen species have often been found to be elevated in animal models of chronic kidney disease (27,36). In such models, renal tissue hypoxia has often been observed (37,53) in association with abnormally high renal V O 2 , at least for the prevailing level of sodium reabsorption in the diseased kidney (12). Furthermore, scavengers of reactive oxygen species have often been found to increase the oxygen tension in both the cortex and medulla (37) while reducing renal V O 2 .…”

Section: Discussionmentioning

confidence: 99%

Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease

Abdelkader

Hilliard

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Ow CP, Abdelkader A, Hilliard LM, Phillips JK, Evans RG. Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease. Am J Physiol Regul Integr Comp Physiol 307: R1207-R1215, 2014. First published September 10, 2014 doi:10.1152/ajpregu.00202.2014.-Renal tissue oxygen tension (PO2) and its determinants have not been quantified in polycystic kidney disease (PKD). Therefore, we measured kidney tissue PO2 in the Lewis rat model of PKD (LPK) and in Lewis control rats. We also determined the relative contributions of altered renal oxygen delivery and consumption to renal tissue hypoxia in LPK rats. PO2 of the superficial cortex of 11-to 13-wk-old LPK rats, measured by Clark electrode with the rat under anesthesia, was higher within the cysts (32.8 Ϯ 4.0 mmHg) than the superficial cortical parenchyma (18.3 Ϯ 3.5 mmHg). PO2 in the superficial cortical parenchyma of Lewis rats was 2.5-fold greater (46.0 Ϯ 3.1 mmHg) than in LPK rats. At each depth below the cortical surface, tissue PO2 in LPK rats was approximately half that in Lewis rats. Renal blood flow was 60% less in LPK than in Lewis rats, and arterial hemoglobin concentration was 57% less, so renal oxygen delivery was 78% less. Renal venous PO2 was 38% less in LPK than Lewis rats. Sodium reabsorption was 98% less in LPK than Lewis rats, but renal oxygen consumption did not significantly differ between the two groups. Thus, in this model of PKD, kidney tissue is severely hypoxic, at least partly because of deficient renal oxygen delivery. Nevertheless, the observation of similar renal oxygen consumption, despite markedly less sodium reabsorption, in the kidneys of LPK compared with Lewis rats, indicates the presence of inappropriately high oxygen consumption in the polycystic kidney. chronic kidney disease; anoxia; ischemia; oxygen; oxygen consumption; oxygen delivery; renal circulation POLYCYSTIC KIDNEY DISEASE (PKD) is characterized by enhanced proliferation of the epithelium (25) resulting in the formation of renal cysts (20), renomegaly (50), and abnormalities of the renal vasculature (3, 52). Renal tissue hypoxia also appears to be characteristic of PKD, having been demonstrated using pimonidazole adduct immunohistochemistry, an indirect method for assessing tissue oxygenation (4, 10). These observations indicate that hypoxia is present throughout the renal parenchyma, but that the epithelium lining the cysts is particularly hypoxic (2, 4, 10). However, we are not aware of any previous studies in which renal tissue oxygen tension (PO 2 ) has been measured directly in PKD. Renal hypoxia might be important in PKD in at least two respects. First, there is evidence that in chronic kidney disease renal tissue hypoxia can activate sensory nerves within the kidney to activate the sympathetic nervous system (18). Second, hypoxia may exacerbate progression of PKD by hypoxia-inducible factor-dependent cystogenesis (6, 41).In chronic kidney disease, an imbalance between renal oxygen delivery (DO 2 ) and consumption (V O 2 ), the main determinants of ...

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“…PTC were isolated from normoglycemic controls and diabetic rats as previously described (5). Briefly, kidney cortex was minced through a metallic mesh strainer and incubated with ice-cooled buffer solution containing collagenase (0.05% wt/vol) at 37°C for 90 min while the suspension was bubbled with a mixture of 95% O 2 and 5% CO2.…”

Section: Measurement Of Gfr Rbf LImentioning

confidence: 99%

“…The diabetic kidney has an altered oxygen metabolism leading to reduced oxygen tension (PO 2 ) throughout the kidney (29). It is also reported that isolated proximal tubular cells (PTC) from diabetic rats have increased transport-dependent oxygen consumption (QO 2 ) and increased phosphorylation of the regulatory NADPH oxidase subunits p47 phox and p22 phox (1,5,7). Superoxide radicals (O 2 ·Ϫ ) increase intracellular Na ϩ by stimulating the sodium/potassium/2-chloride (NKCC2) transporter in medullary thick ascending limbs (mTAL) (15).…”

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confidence: 99%

NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes

Persson

Hansell

Palm

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Persson P, Hansell P, Palm F. NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes. Am J Physiol Regul Integr Comp Physiol 302: R1443-R1449, 2012. First published May 2, 2012 doi:10.1152/ajpregu.00502.2011.-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 ϩ transport and kidney PO2 in vivo. Glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), Na ϩ excretion, fractional Li ϩ excretion, and intrarenal PO2 was measured in control and streptozotocin-diabetic rats during baseline and after acute NA-DPH 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 Ϯ 0.3 vs. 1.4 Ϯ 0.1 ml·min Ϫ1 ·kidney Ϫ1 ). 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 Ϯ 0.7 vs. 42.5 Ϯ 1.2 mmHg and 15.7 Ϯ 1.2 vs. 25.5 Ϯ 2.3 mmHg, respectively). Na ϩ excretion was increased in diabetics compared with controls (24.0 Ϯ 4.7 vs. 9.0 Ϯ 2.0 m·min Ϫ1 ·kidney Ϫ1 ). In controls, all parameters were unaffected. However, apocynin increased Na ϩ excretion (ϩ112%) and decreased fractional lithium reabsorption (Ϫ10%) in diabetics, resulting in improved cortical (ϩ14%) and medullary (ϩ28%) PO 2. QO2 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, NA-DPH oxidase inhibition reduces tubular Na ϩ transport and improves intrarenal PO 2 in diabetes.

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The roles of NADPH‐oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney

Cited by 31 publications

References 24 publications

Wld^Sameliorates renal injury in a type 1 diabetic mouse model

Wld^Sameliorates renal injury in a type 1 diabetic mouse model

Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease

NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes

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The roles of NADPH‐oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney

Cited by 31 publications

References 24 publications

WldSameliorates renal injury in a type 1 diabetic mouse model

WldSameliorates renal injury in a type 1 diabetic mouse model

Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease

NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes

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Product

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Wld^Sameliorates renal injury in a type 1 diabetic mouse model

Wld^Sameliorates renal injury in a type 1 diabetic mouse model