Effect of Semaglutide-Induced Prolonged Activation of Glucagon-Like Peptide-1 Receptors on Sodium Balance in Rats

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat type 2 diabetes mellitus and obesity, promoting glycemic control and body weight reduction. Beyond its metabolic effects, GLP-1 is known to influence renal function and water-electrolyte balance. Currently, long-acting GLP-1 agonists with a half-life of about one week are being increasingly used; however, their natriuretic action remains unexplored. This study was aimed to evaluate the effects of semaglutide-induced prolonged activation of GLP-1 receptors on water-salt metabolism in healthy rats, including changes in renal sensitivity to NaCl loads and diuretics. The study was carried out on sexually mature Wistar rats of both sexes (20 males and 140 females); semaglutide was administered at doses of 0.125–8 nmol per 100 g body weight. It was shown for the first time that semaglutide exerts a pronounced diuretic and natriuretic effect in rats, particularly during the first 2 h post-injection, with increased sodium excretion persisting for at least 8 h. A higher renal sensitivity to semaglutide was revealed in females. Following semaglutide administration, food intake decreased 2.1–2.7-fold over two days, water intake decreased 2.5-fold over the first day, and NaCl solution intake decreased 5–30-fold over three days. The concomitant increase in serum total protein and albumin levels during this period indicates hemoconcentration and, presumably, the development of hypovolemia. At 48 and 72 h following semaglutide administration, the natriuretic response to NaCl loading was reduced, the efficacy of furosemide was increased, and the efficacy of hydrochlorothiazide was decreased. This likely reflects compensatory responses of tubular sodium transport, specifically, increased sodium reabsorption in the thick ascending limb of the loop of Henle. The obtained data indicate the development of sodium deficiency in the body over three days following the administration of a long-acting GLP-1 agonist, which may have clinical implications for the therapy of cardiovascular diseases.