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The Role of Kidney Oxygen Homeostasis for the Development of Kidney Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The relation between oxygen supply and demand determines tissue oxygen tension (PO2). When intrarenal tissue PO2 decreases, any compensatory increase in oxygen supply via increased renal blood flow is likely to increase glomerular filtration rate. The resulting increased tubular load of electrolytes destined for active transport increases oxygen consumption, thus affecting intrarenal tissue PO2. Consequently, the kidney is particularly sensitive to alterations in oxygen homeostasis and kidney hypoxia is acknowledged as a common pathway to end stage renal disease. Different factors that can affect intrarenal oxygen homeostasis, including alterations in blood pressure and sodium intake dietary or pathologies such as diabetes mellitus, anemia or atherosclerosis. This thesis focuses on understanding how these factors influence kidney oxygen homeostasis.

Pronounced reduction in sodium intake caused tissue hypoxia in kidney cortex via activation of the renin-angiotensin-aldosterone leading to increased tubular sodium reabsorption. Angiotensin II and aldosterone affect kidney oxygen handling differently. Whereas angiotensin II mainly affects kidney oxygen delivery, aldosterone mainly affects oxygen consumption.

The hypoxia-inducible factor (HIF) system is a cellular defense mechanism against prolonged hypoxia. Although diabetes causes intrarenal hypoxia, hyperglycemia per se also prevents HIF-activation. Therefore, the effects of type 1 diabetes were evaluated in genetically modified mice with chronic HIF-activation. Diabetic mice with globally increased HIF activity, due to heterozygote prolyl hydroxylase-2 deficiency, displayed reduced mitochondria leak respiration and preserved cortical PO2. Diabetic mice with kidney-specific HIF activation, due to homozygous deficiency of von Hippel-Lindau, developed reduced mitochondria leak respiration and reduced urinary albumin excretion.

The normal age-related decline in kidney function has been proposed to be due to, at least in part, increased oxidative stress, which can induce mitochondrial leak respiration via activation of uncoupling proteins. Indeed, two-year old mice deficient of uncoupling protein-2 presented with improved mitochondria efficiency and reduced urinary protein excretion.

Summarizing, the data presented in this thesis provide clear support for potent influence of the renin-angiotensin-aldosterone system, HIF activation and mitochondria function on intrarenal oxygen availability. Maintaining kidney oxygen homeostasis may be a unifying strategy to protect kidney function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1581
Keywords [en]
Oxygen, Kidney mitochondria, Hypoxia-inducible factors, Prolyl hydroxylase, von Hippel-Lindau, Diabetes, Aging, Kidney, Sodium, RAAS
National Category
Basic Medicine
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-387389ISBN: 978-91-513-0691-9 (print)OAI: oai:DiVA.org:uu-387389DiVA, id: diva2:1328798
Public defence
2019-09-06, C2:305, Biomedicinsk Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-08-16 Created: 2019-06-23 Last updated: 2019-09-17
List of papers
1. Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin AT1 and aldosterone receptor blockade
Open this publication in new window or tab >>Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin AT1 and aldosterone receptor blockade
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387381 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23
2. Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic mice
Open this publication in new window or tab >>Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic mice
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387385 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23
3. Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice
Open this publication in new window or tab >>Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387387 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23
4. Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretion
Open this publication in new window or tab >>Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretion
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-387388 (URN)
Available from: 2019-06-23 Created: 2019-06-23 Last updated: 2019-06-23

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