Angiotensin II and salt-induced decompensation in Balb/CJ mice is aggravated by fluid retention related to low oxidative stress

Abstract

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.

Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome

“…In a previous study, focusing on the renal response to ANG II and high-salt diet in Balb/CJ and C57BL/6J, we found that Balb/CJ mice retain more sodium and water compared with C57BL/6J mice (14). However, we did not find any systematic effects on glomerular filtration rate, indicating that severe renal failure is probably not the cause of the high mortality.…”

“…In addition, the surgery to implant the osmotic minipump is an additional stressor and probably contributes to the initial weight decrease. Interestingly, stress seems to be part of the model as we find slightly improved survival in animals that do not undergo as many investigations; for example, the animals used for earlier microarray experiments (14). ANG II is known to induce cardiac hypertrophy irrespective of its effect on systemic blood pressure (1,18).…”

“…Therefore, in all following experiments, the ANG II dose was reduced to 0.5 g•min Ϫ1 •kg Ϫ1 and sodium content in food to 3%. Mortality data presented in this paper have previously been used in a meta-analysis to estimate the overall effect of ANG II ϩ Salt on mortality in Balb/CJ and C57BL/6J (14). However, time-to-event mortality data are presented here, because of its importance in relation to the sequential cardiac function measurements.…”

“…Study design and treatment. Mortality frequency from the preliminary study was included in a previous publication (14), but time-toevent data were deemed important in relation to present study of the decompensation time course. In the preliminary study sham operated animals and animals treated with a combination of 1 g•min Ϫ1 •kg Ϫ1 ANG II and 4% sodium diet for 5 wk were used.…”

Cardiac and respiratory muscle responses to dietary N-acetylcysteine in rats consuming a high-saturated fat, high-sucrose diet

“…However, visual and manual inspection suggested that all rats had normal hydration throughout the study. NAC administration lowers urine water excretion in angiotensin II-treated mice, 90 and direct kidney perfusion with antioxidant promotes water retention in spontaneously hypertensive rats. 91 The lower water consumption by HFHS+NAC rats may have been a compensatory mechanism to maintain euhydration.…”