Altered Water Handing in Mice Following Chronic Aldosterone Administration

Abstract

Aldosterone is a steroid hormone that is necessary for sodium and water reabsorption in the distal tubules and collecting ducts of the kidney that is released in response to changes in volume and potassium levels. While aldosterone is typically associated with fluid retention due to its role in promoting sodium reabsorption, previous work has shown that aldosterone further exacerbates urine production in a rat model of diabetes insipidus. Because of this, we aimed to understand the effects of chronic aldosterone administration in mice with no underlying pathology to further elucidate the effects of chronic aldosterone administration on water reabsorption in the kidneys. Aldosterone was administered at a dose of 240 μg/kg/day via subcutaneous minipump to C57Bl/6 male mice housed in metabolic cages. By Day 15, mice given aldosterone had increased urine output compared to control animals (Ctl 4.8 ± 1.6 mL; Aldo 8.4 ± 2.4 mL), and this difference persisted through day 28. The aldosterone treated animals trended toward drinking more water starting at day 7, however significance was not obtained. To understand whether these animals were producing concentrated urine, we measured urine osmolality by freeze‐point depression. By Day 4, there was a significant decrease in daytime urine osmolality in the aldosterone administered mice compared to the control mice (Ctl 1219.8 ± 473.4 mOsm/kg; Aldo 638.8 ± 143.8 mOsm/kg), and by day 17, there was also a significant decrease in nighttime urine osmolality of the aldosterone treated versus control mice (Ctl 905.3 ± 175.1 mOsm/kg; Aldo 522.2 ± 127.3 mOsm/kg). Mice receiving aldosterone had a higher whole blood [Na+] (Ctl 146 ± 1.9mmol/L; Aldo 152 ± 1.3mmol/L) and lower whole blood [K+] (Ctl 4.8 ± 0.56mmol/L; Aldo 3.0 ± 0.34mmol/L) as measured by iSTAT cartridge after terminal cardiac blood draw. At a molecular level, a significant increase (~3.5 fold) in Aqp4 whole kidney mRNA levels were measured in the aldosterone treated mice compared to the control mice at both 2 weeks and 4 weeks of treatment. Additionally, Aqp1 and Aqp3 mRNA levels trended toward being lower in the aldosterone treated animals although significance was not reached. Aqp2 levels were variable, but unchanged at a transcript level. Protein expression and localization of these aquaporins are currently being investigated by Western blot and immunofluorescent staining. Together, these data indicate that chronic aldosterone administration causes a diuresis with decreased concentrating ability. We are currently testing whether correction of the serum [K+] corrects the concentrating defect, and whether vasopressin is involved in these responses.