All ETDs from UAB

Advisory Committee Chair

David M Pollock

Advisory Committee Members

Shannon M Bailey

Orlando M Gutierrez

Courtney M Peterson

Jennifer S Pollock

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The renal endothelin system plays a key role in sodium excretion, particularly under high salt (HS) diet. HS stimulates renal endothelin-1 (ET-1), which binds and activates the endothelin receptor B (ETB) to excrete the excess salt. Loss of ETB receptor is linked to the development of hypertension under HS. Central clock genes are important in maintaining rhythmic patterns of sodium excretion and ET-1 is identified as a target for clock genes, including Period and Bmal1. ET-1 excretion follows a diurnal rhythm along with sodium excretion. Sexual dimorphism is evident in the diurnal regulation of endothelin-mediated natriuresis and its downstream targets. Obesity enhances sodium reabsorption leading to the development of hypertension. However, the role of renal ET-1 diurnal rhythms in obesity is poorly understood. Recent studies showed that Dahl salt-sensitive (Dahl SS) rats on HF diet have impaired ETB-mediated natriuresis. However, whether this impairment occurs in obesity in general is not known. The overarching hypothesis of this dissertation is that diet-induced obesity impairs diurnal renal salt handling ability that is associated with renal ET-1 dysfunction in a sex-specific manner. After 8 weeks of high fat (HF) diet, male rats had significantly reduced natriuresis in response to an acute NaCl injection when given at the beginning of their active period. This was mirrored by lower ET-1 excretion and lower ET-1 mRNA expression in the kidneys of HF-treated rats. HF-treated males had higher blood pressure and developed salt sensitivity on HS diet. Females fed a HF diet showed intact acute natriuretic response and ET-1 excretion rates similar to normal fat (NF) controls. While female rats developed hypertension on HF diet, they were not salt sensitive, which points out a clear sex difference in response to diet-induced obesity and suggests that obesity-associated hypertension is ET-1 independent in female rats. In addition, females fed regular chow had a lower natriuretic response to blockade of ET-1 downstream target channel, ENaC, by benzamil compared to males at different times of day. In conclusion, our study demonstrates that HF diet modulates renal ET-1 system and highlights this impairment as a potential mechanism in the development of obesity-induced hypertension.

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