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Diabetes-induced Alterations in Renal Microcirculation and Metabolism
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function is unclear, although several hypotheses have been postulated. Glucose-induced excessive formation of reactive oxygen species (ROS) and increased glucose flux through the polyol pathway are two major mechanisms that have recently gained increasing support. In order to investigate the development of hyperglycaemia-induced renal alterations further, it is of great importance to use an animal model in agreement with the pathological development in diabetic patients.

The aims of these investigations were to evaluate the streptozotocin (STZ)-diabetic Wistar Furth rat as a model for human diabetic nephropathy and to investigate involvement of ROS and the polyol pathway in development of diabetes-induced renal alterations.

The used STZ-diabetic animal model displayed several similarities with the progression of human disease, including initial hyperfiltration and albuminuria. However, the observed proteinuria could be partly linked to the STZ treatment per se, making the use of this animal model less suitable for research concerning diabetes-induced urinary protein leakage.

The diabetic state induced numerous alterations in renal function and metabolism, including increased oxygen consumption, decreased renal oxygen tension (pO2), and altered lactate/pyruvate ratio. These renal alterations were preventable by daily treatment with either a radical scavenger (α-tocopherol) or an aldose reductase inhibitor (AL-1576).

In separate experiments the influence of nitric oxide (NO) on renal blood perfusion and pO2 was investigated. The diabetic animals displayed a larger increase in renal NO activity after injecting the NO substrate L-arginine compared to non-diabetic animals, suggesting substrate limitation of the nitric oxide synthase during chronic hyperglycaemia.

In conclusion, the results from these investigations show that both ROS and the polyol pathway are involved in the development of diabetes-induced renal alterations in the STZ- diabetic Wistar Furth rat.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 45
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1358
Keywords [en]
Physiology, diabetes mellitus, kidney, nephropathy, oxygen tension, haemodynamic, nitric oxide, oxygen consumption, radical oxygen species, polyol pathway
Keywords [sv]
Fysiologi
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-4285ISBN: 91-554-5985-4 (print)OAI: oai:DiVA.org:uu-4285DiVA, id: diva2:164710
Public defence
2004-05-24, Sal IV, Universitetshuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-05-03 Created: 2004-05-03 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Transient glomerular hyperfiltration in the streptozotocin-diabetic Wistar Furth rat
Open this publication in new window or tab >>Transient glomerular hyperfiltration in the streptozotocin-diabetic Wistar Furth rat
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2001 In: Upsala J. Med. Sci., Vol. 106, p. 175-182Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91844 (URN)
Available from: 2004-05-03 Created: 2004-05-03Bibliographically approved
2. Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model
Open this publication in new window or tab >>Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model
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2004 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 20, no 6, p. 452-459Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The animal model with streptozotocin (STZ)-induced diabetes mellitus is associated with progressive renal disturbances. The aim of this study was to differentiate between toxic effects of STZ and the effect of hyperglycemia. Previous studies have been limited to investigating the influence of STZ on glomerular filtration rate (GFR), albuminuria and renal morphology. The present study presents a new approach when transplanting beta-cells to cure the STZ-treated animals and extends the evaluation to include both renal function and oxygen metabolism.

METHODS:

Animals were allocated to three groups: control animals, STZ-diabetic animals and animals rendered diabetic with an injection of STZ, followed by immediate syngeneic transplantation of approximately 1000 pancreatic islets into the splenic parenchyma. This latter procedure reversed the hyperglycemia induced by STZ. Renal function was evaluated from GFR and urinary albumin and protein leakage, while regional renal blood flow was determined using a laser-Doppler technique and oxygen tension measured with Clark-type electrodes.

RESULTS:

In diabetic animals, GFR increased, renal oxygen tension decreased and renal hypertrophy occurred, along with urinary leakage of protein, including albumin. Early transplantation of pancreatic islets to STZ-treated animals prevented the development of all these changes, except for proteinuria. However, an analysis of urinary protein content revealed that albuminuria was preventable by islet transplantation.

CONCLUSIONS:

We conclude that the urinary protein leakage in this animal model is at least partly due to direct toxic effects of STZ, whereas the other renal changes investigated in this study are due to the long-term diabetic condition.

Keywords
Animals, Diabetes Mellitus; Experimental/complications/metabolism/pathology/*physiopathology/surgery, Glomerular Filtration Rate, Hyperglycemia/*physiopathology, Islets of Langerhans Transplantation, Kidney/*drug effects/metabolism/pathology/*physiopathology, Male, Natriuresis, Oxygen/metabolism, Potassium/urine, Proteinuria/etiology, Rats, Rats; Wistar, Research Support; Non-U.S. Gov't, Streptozocin/*pharmacology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91845 (URN)10.1002/dmrr.472 (DOI)15386825 (PubMedID)
Available from: 2004-05-03 Created: 2004-05-03 Last updated: 2017-12-14Bibliographically approved
3. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension
Open this publication in new window or tab >>Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension
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2003 In: Diabetologia, Vol. 46, p. 1153-1160Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91846 (URN)
Available from: 2004-05-03 Created: 2004-05-03Bibliographically approved
4. Polyol pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats
Open this publication in new window or tab >>Polyol pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats
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2004 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 47, no 7, p. 1223-1231Article in journal (Refereed) Published
Abstract [en]

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 purine-based 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.

Keywords
Aldose reductase, Kidney, Metabolism, Microcirculation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91847 (URN)10.1007/s00125-004-1434-3 (DOI)
Available from: 2004-05-03 Created: 2004-05-03 Last updated: 2017-12-14Bibliographically approved
5. The effect of nitric oxide on renal microcirculation, oxygenation and function in streptozotocin-induced diabetes mellitus
Open this publication in new window or tab >>The effect of nitric oxide on renal microcirculation, oxygenation and function in streptozotocin-induced diabetes mellitus
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91848 (URN)
Available from: 2004-05-03 Created: 2004-05-03 Last updated: 2010-01-13Bibliographically approved

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