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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
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-387385OAI: oai:DiVA.org:uu-387385DiVA, id: diva2:1328768
Tillgänglig från: 2019-06-23 Skapad: 2019-06-23 Senast uppdaterad: 2019-06-23
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1. The Role of Kidney Oxygen Homeostasis for the Development of Kidney Disease
Öppna denna publikation i ny flik eller fönster >>The Role of Kidney Oxygen Homeostasis for the Development of Kidney Disease
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 56
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1581
Nyckelord
Oxygen, Kidney mitochondria, Hypoxia-inducible factors, Prolyl hydroxylase, von Hippel-Lindau, Diabetes, Aging, Kidney, Sodium, RAAS
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Forskningsämne
Fysiologi
Identifikatorer
urn:nbn:se:uu:diva-387389 (URN)978-91-513-0691-9 (ISBN)
Disputation
2019-09-06, C2:305, Biomedicinsk Centrum, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-08-16 Skapad: 2019-06-23 Senast uppdaterad: 2019-09-17

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Schiffer, Tomas A.Hansell, PeterFriederich, MalouPalm, Fredrik

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Schiffer, Tomas A.Hansell, PeterFriederich, MalouPalm, Fredrik
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Institutionen för medicinsk cellbiologiIntegrativ Fysiologi
Medicin och hälsovetenskap

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