All ETDs from UAB

Advisory Committee Chair

David M Pollock

Advisory Committee Members

Shannon M Bailey

Jennifer S Pollock

Paul W Sanders

Martin E Young

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Healthy individuals typically have a diurnal rhythm in sodium (Na+) excretion, with levels higher during the daytime and lower at nighttime. While the mechanism behind this rhythm is not yet fully understood, molecular clock genes such as Bmal1 may contribute to the diurnal variation in urinary Na+ excretion (UNaV). Endothelin-1 (ET-1) is a peptide that aids in the regulation of Na+ balance through activation of the endothelin B (ETB) receptor. Although the ETB receptor has been shown to play an important role in promoting natriuresis, whether this varies according to time of day is unknown. This dissertation examines the role of ET-1 through the ETB receptor in the diurnal regulation of Na+ excretion in rats. Since mechanisms regulating Na+ excretion are sex dependent, it is also important to determine if there are sex differences in diurnal control. Specifically, the impact of Bmal1 of the diurnal regulation of Na+ excretion in acute and chronic salt loading settings was studied using a novel Bmal1-/- rat model. Along with this, the functional significance of the interaction between ET-1 and Bmal1 was tested as well. A major finding from these studies is that ETB receptor deficient (ETB def) rats have a delayed natriuretic response to an acute salt load (900µEq Na+) that is time-of-day dependent. In addition, females are more efficient in excreting the excess salt. In both sexes, the ETA receptor contributes to this impaired natriuretic response as well. Male, but not female, Bmal1-/- rats have an impaired diurnal rhythm in Na+ excretion. Loss of Bmal1 does not impact the rhythm of mean arterial pressure (MAP) in these rats despite them having an overall reduction in MAP throughout the day. Bmal1-/- rats showed reduced UNaV during chronic salt feeding, however ETB blockade did not appear to influence UNaV despite similar BP between genotypes. Overall, this dissertation provides new evidence that ET-1 and the ETB receptor are required for the renal excretion of an acute salt load that is time-of-day- and sex-dependent. This pathway appears to regulate UNaV independent of Bmal1 in rats, suggesting other circadian factors could be involved.

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