Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension

Palm, Fredrik; Cederberg, Jonas; Hansell, Peter; Liss, Per; Carlsson, Per‐Ola

doi:10.1007/s00125-003-1155-z

Cited by 273 publications

(323 citation statements)

References 51 publications

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“…In view of our previous [8] and present results with markedly decreased renal tissue oxygen tension during chronic hyperglycaemia, we conducted separate experiments applying microdialysis to assess the regional interstitial metabolic environment in vivo. Increased lactate levels were observed in the renal medulla of the diabetic animals.…”

Section: Discussionmentioning

confidence: 99%

“…For non-diabetic rats, the buffer contained 5.8 mmol/l glucose, and for diabetic animals the buffer contained 23.2 mmol/l glucose (similar to the blood glucose concentrations in the latter animals). The renal cells were isolated as previously described [8,17,18]. In brief, the rats were anaesthetised with thiobutabarbital, the kidneys were excised and the renal capsule was removed.…”

Section: Isolation Of Renal Cells and Measurement Of In Vitro Oxygen mentioning

confidence: 99%

“…Oxygen consumption was measured as previously described [8,18]. In brief, a custom-made thermostatically controlled (37°C) gas-tight plexi-glass chamber with a total volume of 1.100 ml was used.…”

Section: Isolation Of Renal Cells and Measurement Of In Vitro Oxygen mentioning

confidence: 99%

“…We have recently shown that reactive oxygen species (ROS) play an important role in the development of hyperglycaemia-induced alterations in renal oxygen metabolism [8]. Oxidative stress, closely associated with excessive formation of ROS, was predominantly found in the renal medulla and was related to increased oxygen consumption and decreased tissue oxygen tension.…”

Section: Introductionmentioning

confidence: 99%

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Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

et al. 2004

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Aims/hypothesis. The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Methods. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purinebased metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes.Results. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Conclusions/interpretation. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

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Section: Discussionmentioning

confidence: 99%

Section: Isolation Of Renal Cells and Measurement Of In Vitro Oxygen mentioning

confidence: 99%

Section: Isolation Of Renal Cells and Measurement Of In Vitro Oxygen mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

et al. 2004

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“…Chronic hypoxia of the diabetic kidney was demonstrated by pimonidazole [33], measurement with a microelectrode [34], and blood-oxygen level-dependent magnetic resonance imaging [35]. We established the hypoxia-sensing transgenic rats expressing the HRE-driven luciferase vector tagged with FLAG.…”

Section: Chronic Kidney Diseasementioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

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Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

211

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension

Cited by 273 publications

References 51 publications

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

Hypoxia and the HIF system in kidney disease

Pathophysiology of the Diabetic Kidney

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