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Angiotensin II and salt-induced decompensation in Balb/CJ mice is aggravated by fluid retention related to low oxidative stress
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Michael Hultström)ORCID iD: 0000-0002-1110-9488
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 Sciences, Cardiology.
Department of Biomedicine, University of Bergen, Bergen, Norway.
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2019 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 5, p. F914-F933Article in journal (Refereed) Published
Abstract [en]

Balb/CJ mice are more sensitive to treatment with angiotensin II (ANG II) and high-salt diet compared with C57BL/6J mice. Together with higher mortality, they develop edema, signs of heart failure, and acute kidney injury. The aim of the present study was to identify differences in renal gene regulation that may affect kidney function and fluid balance, which could contribute to decompensation in Balb/CJ mice after ANG II + salt treatment. Male Balb/CJ and C57BL/6J mice were divided into the following five different treatment groups: control, ANG II, salt, ANG II + salt. and ANG II + salt + N-acetylcysteine. Gene expression microarrays were used to explore differential gene expression after treatment and between the strains. Published data from the Mouse Genome Database were used to identify the associated genomic differences. The glomerular filtration rate (GFR) was measured using inulin clearance, and fluid balance was measured using metabolic cages. Gene ontology enrichment analysis of gene expression microarrays identified glutathione transferase (antioxidant system) as highly enriched among differentially expressed genes. Balb/CJ mice had similar GFR compared with C57BL/6J mice but excreted less Na+ and water, although net fluid and electrolyte balance did not differ, suggesting that Balb/CJ mice may be inherently more prone to decompensation. Interestingly, C57BL/6J mice had higher urinary oxidative stress despite their relative protection from decompensation. In addition, treatment with the antioxidant N-acetylcysteine decreased oxidative stress in C57BL/6J mice, reduced urine excretion, and increased mortality. Balb/CJ mice are more sensitive than C57BL/6J to ANG II + salt, in part mediated by lower oxidative stress, which favors fluid and Na+ retention.

Place, publisher, year, edition, pages
2019. Vol. 316, no 5, p. F914-F933
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-379717DOI: 10.1152/ajprenal.00483.2018ISI: 000467160100016PubMedID: 30785350OAI: oai:DiVA.org:uu-379717DiVA, id: diva2:1297598
Funder
Åke Wiberg FoundationSwedish Heart Lung FoundationSwedish Society of MedicineSwedish Society for Medical Research (SSMF)EU, FP7, Seventh Framework ProgrammeAvailable from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-06-10Bibliographically approved
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)
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Available from: 2019-04-17 Created: 2019-03-20 Last updated: 2019-06-17

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Jönsson, SofiaAgic, Mediha BecriovicHultström, Michael

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