Sex Differences in Diurnal Sodium Handling During Diet-Induced Obesity in Rats

Abstract

Background: Emerging evidence over the past several years suggests that diurnal control of sodium excretion is sex dependent and involves the renal endothelin system. Given recent awareness of disruptions of circadian function in obesity, we determined whether diet-induced obesity impairs renal handling of an acute salt load at different times of day and whether this varies by sex and is associated with renal endothelin dysfunction. Methods: Male and female Sprague-Dawley rats were placed on a high-fat diet for 8 weeks before assessing renal sodium handling and blood pressure. Results: Male, but not female, rats on high fat had a significantly reduced natriuretic response to acute NaCl injection at the beginning of their active period that was associated with lower endothelin 1 (ET-1) excretion, lower ET-1 mRNA expression in the cortex and outer medulla as well as lower ET B receptor expression in the outer medulla of the high-fat rats. Obese males also had significantly higher blood pressure (telemetry) that was exacerbated by adding high salt to the diet during the last 2 weeks. While female rats developed hypertension with a high-fat diet, they were not salt sensitive and ET-1 excretion was unchanged. Conclusions: These data identify diet-induced obesity as a sex-specific disruptive factor for maintaining proper sodium handling. Although high-fat diets induce hypertension in both sexes, these data reveal that males are at greater risk of salt-dependent hypertension and further suggest that females have more redundant systems that can be productive against salt-sensitive hypertension in at least some circumstances.

Mice lacking γENaC palmitoylation sites maintain benzamil-sensitive Na+ transport despite reduced channel activity

“…Na + restriction induced higher aldosterone levels in male γ C33A,C41A versus WT mice (Figure 4), which was likely a compensatory response to impaired ENaC function, although we did not observe a similar effect in females. Sex differences associated with epithelial ion transport regulation are known to play a major role in the adaptive responses to various dietary manipulations (40,(60)(61)(62)(63). Increases in aldosterone levels in response to Na + restriction are more modest in female versus male rats (64).…”