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Angiotensin II and salt-induced decompensation in Balb/CJ mice is associated with genetic differences in glutathione transferase activity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Department of Biomedicine, University of Bergen, Bergen, Norway.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-379720OAI: oai:DiVA.org:uu-379720DiVA, id: diva2:1297609
Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-04-01
In thesis
1. The Role of Angiotensin II in Experimental Acute Kidney Injury and Cardiorenal Failure
Open this publication in new window or tab >>The Role of Angiotensin II in Experimental Acute Kidney Injury and Cardiorenal Failure
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Blood pressure and fluid regulation are kept constant through the interaction between heart and kidneys. When the systemic blood pressure decreases, the levels of the hormone Angiotensin II increase, leading to vasoconstriction and therefore increased blood pressure. Angiotensin II may act directly on the vessels or cause fluid retention in the kidneys, consequently increasing blood pressure. Dysfunctional heart and kidneys lead to different diseases, such as heart failure and acute kidney injury. A failing heart can cause damage to kidneys and vice versa, leading to cardiorenal syndrome. Due to the severity of these diseases and their increasing prevalence, it is important to investigate them further. Therefore, the aim of this thesis was to evaluate blockage or treatment of Angiotensin II on the effects on renal and cardiac function.

Study I investigates the effect of Losartan, an Angiotensin receptor blocker, on kidney oxygenation as well as the effect on blood pressure, after resuscitated haemorrhage and Norepinephrine administration. It showed that Losartan does not worsen the effects of kidney oxygenation. The blood pressure managing affects of Norepinephrine were also not worsened in rats treated with Losartan.

Study II-IV investigate treatment of Angiotensin II and high salt diet on renal and cardiac function in Balb/CJ and C57BL/6J mice. This treatment showed increased mortality in Balb/CJ mice compared to C57BL/6J. Balb/CJ also retained more fluid and sodium than C57BL/6J and had worsened cardiac function after Angiotensin II and salt treatment. These are signs of heart failure and decompensation. Balb/CJ had lower amount of oxidative stress, compared to C57BL/6J. Treating the latter with the antioxidant N-acetylcysteine, reduced the levels of oxidative stress, but increased the mortality.

In conclusion, Angiotensin II treatment or blockage has different effects on both renal function as well as cardiac function, depending on strain and treatment settings.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1554
Keywords
Heart failure, Acute kidney injury, Angiotensin II, Fluid balance, Cardiac function, Renal function
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-379723 (URN)978-91-513-0602-5 (ISBN)
Public defence
2019-05-09, C4:305, Biomedicinskt Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-04-17 Created: 2019-03-20 Last updated: 2019-06-17
2. Susceptibility to Acute Decompensated Heart Failure in Two Common Mouse Strains
Open this publication in new window or tab >>Susceptibility to Acute Decompensated Heart Failure in Two Common Mouse Strains
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heart failure is a clinical syndrome characterized by an inability of the heart to meet oxygen demands of the body. During the initial stage of heart failure development compensatory mechanisms are activated to help the heart sustain proper function. Over time these compensatory mechanisms become inadequate resulting in decompensation. Acute decompensated heart failure is characterized by rapidly escalating heart failure symptoms, such as dyspnea and congestion, which require urgent treatment. The pathophysiology of decompensation and role of genetic background on this process is not completely understood.  The aim of this thesis was to investigate the role of genetic background on susceptibility to develop acute decompensated heart failure.

Balb/CJ and C57BL/6J mice are two common mouse strains that we found have different susceptibility to angiotensin II and high-salt diet (AngII+Salt) induced decompensation. Balb/CJ treated with AngII+Salt develop massive edema associated with anuria and high mortality within 4-6 days of treatment, while C57BL/6J mice do not. Due to the clinical symptoms of heart failure we hypothesized that Balb/CJ develop acute decompensated heart failure, and that the genetic background of this strain is responsible for the increased susceptibility to heart failure. AngII+Salt increased pulmonary and systemic vascular resistance, reduced left ventricle filling, and increased sodium and water retention in Balb/CJ mice. Increased pulmonary vascular resistance correlated with a higher angiotensin II response in isolated pulmonary arteries from Balb/CJ compared to C57BL/6J. Cardiac output was lower in Balb/CJ than C57BL/6J during AngII+Salt treatment even though they retained more sodium and water. This indicated that AngII+Salt impairs cardiac function in Balb/CJ mice. Oxidative stress was shown to play a role in AngII+Salt induced acute decompensation since treatment with an antioxidant reduced oxidative stress but impaired cardiac function and increased mortality in both strains. A linkage study was performed to reveal genes that are with high probability related to AngII+Salt induced decompensation in Balb/CJ mice. Quantative trait loci (QTLs) on chromosome 3 and 12 were linked to cardiac dysfunction and QTLs on chromosome 2 and 3 were linked to sodium and fluid balance. Foxo1 was found to be one of candidate genes for further study.

Taken together, the data in this thesis shows that genetic background does play a large role in the development of acute decompensated heart failure. It reveals several candidate genes that could be studied in the setting of acute decompensated heart failure. Finally, it describes a new mouse model that could potentially be used for studying the pathophysiology of decompensation and identifying new drug targets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1562
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-380663 (URN)978-91-513-0622-3 (ISBN)
Public defence
2019-05-27, C2:301, Biomedicinskt centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-04-29 Created: 2019-04-01 Last updated: 2019-06-17

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