[Gastrointestinal metabolic surgery improves salt-sensitive hypertension via GLP-1-mediated inhibition of the...

Objective: To investigate the effect of Roux-en-Y gastric bypass (RYGB) on salt-sensitive hypertension and its underlying molecular mechanism. Methods: (1) Clinical study: A total of 57 patients who underwent RYGB at Daping Hospital, Army Medical University between December 2010 and May 2025 were enrolled. According to the diagnostic criteria for hypertension, the patients were divided into normotensive group and hypertensive group. Baseline and postoperative clinical data were collected. Daily sodium intake was calculated based on 24-hour urinary sodium excretion, and the correlation between preoperative sodium intake and the reduction of postoperative systolic blood pressure was analyzed. (2) Animal experiment: Forty-eight 6-week-old male Dahl salt-sensitive hypertensive rats were fed an 8% high-salt diet for 8 weeks to establish the salt-sensitive hypertension models. Thirty modeled rats were randomly divided into the RYGB group (n=15) and the sham operation group (n=15). The remaining 18 rats were randomly divided into control group (n=6), liraglutide group (n=6) and liraglutide+EX9-39 group (n=6), which were treated with normal saline, liraglutide (0.2 mg·kg^-1·d^-1), and liraglutide combined with EX9-39 (75 μg·kg^-1·d^-1), respectively. Rat blood pressure was measured via non-invasive tail-cuff method and invasive radiotelemetry method, and isolated vascular function was detected. HE, PAS and Masson staining were used to evaluate mesenteric vascular remodeling, glomerular matrix distribution and renal fibrosis degree, respectively. Enzyme-linked immunosorbent assay was adopted to detect serum levels of glucagon-like peptide-1 (GLP-1) and angiotensin Ⅱ (AngⅡ). Western blot was performed to determine the protein expression of tumor necrosis factor-α, interleukin-6, GLP-1 receptor (GLP-1R), angiotensin-converting enzyme (ACE) 1, ACE2, angiotensin Ⅱ type 1 receptor (AGTR1), phosphorylated Na⁺/H⁺ exchanger 3 (NHE3) and total NHE3 in renal cortex. (3) Cell experiments: Rat renal epithelial NRK-52E cells were used. Four experimental groups were set up: high-salt group (treated with 160 mmol/L NaCl for 24 h), high-salt+liraglutide group (100 nmol/L liraglutide), high-salt+liraglutide+EX9-39 group(100 nmol/L liraglutide+150 nmol/L EX9-39), and control group (equal volume of drug vehicle). Western blotting was performed to detect the expression of ACE1, AGTR1, phosphorylated NHE3 and total NHE3. Results: (1) Clinical study: The enrolled patients had an age of (43.91±10.19) years, including 33 males (58%). There were 24 patients in the normotensive group and 33 in the hypertensive group. Compared with the baseline levels, both systolic blood pressure ((133.26±16.48) mmHg vs. (118.23±15.40) mmHg, 1 mmHg=0.133 kPa) and diastolic blood pressure ((83.16±12.44) mmHg vs. (74.54±8.80) mmHg) were decreased after RYGB (both P<0.05). The median daily preoperative sodium intake of all participants was 10.45 (8.19, 15.58) g/d. A positive correlation was observed between preoperative sodium intake and the reduction in postoperative systolic blood pressure (R=0.326, P=0.013). (2) Animal experiment: At the 8th week after surgery, the tail-cuff systolic blood pressure ((125.33±12.16) mmHg vs. (182.00±11.61) mmHg), 24-hour mean systolic blood pressure ((125.81±12.89) mmHg vs. (182.11±10.21) mmHg) and 24-hour mean diastolic blood pressure ((97.36±6.59) mmHg vs. (144.85±16.58) mmHg) in the RYGB group were lower than those in the sham group (all P<0.05). Compared with the sham group, the RYGB group presented a lower ratio of vascular wall thickness to outer vessel diameter, higher vasodilation of mesenteric arteries, and less glomerular collagen deposition. Meanwhile, the levels of serum creatinine, blood urea nitrogen and urinary protein, as well as the expression of tumor necrosis factor-α and interleukin-6 in renal cortex were also lower in RYGB group than sham group (all P<0.05). In addition, compared with sham group, the serum GLP-1 level, renal cortical GLP-1 receptor expression and NHE3 phosphorylation level were higher in the RYGB group, while serum AngⅡ and the expression of ACE1 and AGTR1 in renal cortex were lower (all P<0.05). Drug intervention results showed that tail-cuff systolic blood pressure was lower in the liraglutide group than in the control group ((167.00±9.98) mmHg vs. (182.00±6.26) mmHg, P<0.05). No significant difference in tail-cuff systolic blood pressure was found between the liraglutide+EX9-39 group and the control group (P>0.05). (3) Cell experiments: High-salt treatment upregulated the expression of ACE1 and AGTR1 and inhibited NHE3 phosphorylation in NRK-52E cells. Liraglutide reversed the above abnormalities, whereas EX9-39 antagonized the regulatory effects of liraglutide. Statistically significant differences were observed in the expression levels of the above proteins among all groups (all P<0.05). Conclusion: RYGB can effectively ameliorate salt-sensitive hypertension. The underlying mechanism is associated with GLP-1-mediated inhibition of renin-angiotensin system activity and promotion of NHE3 phosphorylation.