Glucagon-Like Peptide-1 receptor (GLP-1R) blockade elicts salt-dependent blood pressure responses and impairs renal adaptation to high salt intake

We have previously demonstrated that endogenous glucagon-like peptide-1 receptor (GLP-1R) signaling exerts a tonic natriuretic effect that contributes to the regulation of sodium balance and may modulate blood pressure responses. This study tested the hypothesis that GLP-1R blockade induces salt-dependent BP responses and impairs renal adaptive mechanisms to variations in dietary sodium intake. Male Wistar rats were fed a low-salt (LS; 0.03% NaCl), normal-salt (NS; 0.3% NaCl), or high-salt (HS; 4% NaCl) diet for 21 days and treated with the selective GLP-1R antagonist exendin-9 (Ex9; 100 µg/kg/day, i.p.) or saline (Ctrl). Animals were allocated into six groups (Ctrl + LS, Ctrl + NS, Ctrl + HS, Ex9 + LS, Ex9 + NS, and Ex9 + HS). BP was monitored longitudinally by tail-cuff plethysmography and confirmed by direct carotid cannulation at the end of the protocol. Saline-treated rats exhibited similar BP across all diets, consistent with a salt-resistant phenotype. In contrast, GLP-1R blockade induced salt-dependent increases in BP, with Ex9 + HS rats displaying higher BP compared with Ex9 + NS (140 ± 1 vs. 133 ± 1 mmHg, p < 0.0001) and Ex9 + LS (140 ± 1 vs. 128 ± 0.4 mmHg, p < 0.0001). Direct BP measurements confirmed elevated systolic and diastolic pressures in Ex9 + HS compared with Ex9 + LS rats. Renal sodium handling was further assessed by an acute salt-loading challenge. Control rats exhibited a graded natriuretic response to dietary salt, with greater sodium excretion in HS-fed animals compared with NS- and LS-fed groups. This adaptive natriuretic response was blunted under GLP-1R blockade, with significant differences observed only between Ex9 + HS and Ex9 + LS groups, suggesting impaired renal adaptation to sodium overload. At the molecular level, dietary salt intake induced expected changes in sodium transporter regulation in control rats, including increased inhibitory phosphorylation of NHE3 (Ser552) and reduced phosphorylation of NCC (Thr53) in HS-fed animals. In contrast, GLP-1R blockade blunted these diet-dependent responses, abolishing salt-induced differences in NHE3 phosphorylation and attenuating the reduction in NCC phosphorylation across dietary sodium conditions. In conclusion, endogenous GLP-1R signaling contributes to renal and molecular adaptation to dietary sodium intake. GLP-1R blockade impairs sodium transporter remodeling and attenuates natriuretic responses to high salt intake, thereby predisposing to salt-dependent elevations in blood pressure. This abstract was presented at the American Physiology Summit 2026 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.