Sex Differences in Brainstem Astrocyte Protein and Glutamatergic Receptor Expression in High-Salt Diet

The nucleus of the solitary tract (nTS) is the first central location for integrating information from baroreceptors and blood pressure regulation. Baroreceptors release glutamate in the nTS as a response to increased blood pressure, activating glutamatergic receptors. Increased nTS glutamate lowers blood pressure. Astrocytes interact with nTS neurons to form the “tripartite synapse,” allowing astrocytes to influence synaptic plasticity and neuronal activity. Despite extensive research on diet-induced hypertension, our understanding of how dysregulation of nTS astrocytes contributes to this condition, especially in terms of potential sex-specific differences, remains limited, which could impact treatment outcomes. We hypothesized that astrocytes and glutamatergic receptors are altered in a rat model of high-salt diet-induced hypertension and predicted sex differences in the expression of these proteins. To test this hypothesis, we exposed young adult Dahl-salt-sensitive male and female rats (N=43) to a normal-salt diet (NSD, 0.3% NaCl) for two weeks, after which they were randomized to either remain on an NSD or a high-salt diet (HSD, 4% NaCl) for seven weeks. After seven weeks, we used immunohistochemistry (IHC, astrocytes S100B) and immunoblot (astrocytes GFAP, S100B; glutamate receptors GluA1 and NR1) to determine how HSD affects the nTS astrocytes and glutamatergic receptors. First, we confirmed that in HSD, blood pressure increased in males (p=0.03). We then used IHC and confocal imaging to determine that astrocyte number in the nTS increases in HSD in males and females, using S100B (soma marker). Preliminary immunoblot data suggests that high-salt diet increases GLUA1 expression in males (p=0.08) and causes astrocyte changes mediated by increased GFAP (p=0.09) expression. Females, however, were not affected by the high-salt diet (p>0.1). Interestingly, there was a main significant effect of sex for NR1 and GLUA1, where females had higher expression of NR1 (p<0.0001) and GLUA1 (p<0.0001) in both NSD and HSD compared to males. This suggests a distinct response to increased salt intake, which may confer protection against hypertension onsetting. S100 levels, which reflect astrocyte changes, remained unaffected in response to HSD in both sexes. Our data indicates that HSD elevates blood pressure, disrupts nTS astrocytes, and alters GLUA1 and NR1 in males, while these effects are not observed in females. This indicates that HSD may alter nTS function at multiple levels. The mechanisms by which these sex-specific differences occur need further investigation. 23AIREA1057412 to DM; 24DIVSUP1290201 to TG This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.