Acute glucagon infusion induces natriuresis and diuresis through a direct tubular mechanism involving overlapping receptor pathways.

It is unclear whether the reported natriuretic and diuretic effects of glucagon are mediated by renal hemodynamic changes or by direct tubular actions within the kidney. We investigated the renal effects of acute glucagon infusion in rats. We further examined whether these effects are mediated by activation of the glucagon receptor (GCGR) or whether the glucagon-like peptide-1 receptor (GLP-1R) also contributes. Experiments were performed in Sprague-Dawley rats and spontaneously hypertensive rats. Animals received glucagon infusion alone or with selective receptor antagonists targeting GCGR (GRA) or GLP-1R (Exendin9-39). Renal hemodynamics, urine flow, and electrolyte excretion were assessed. Acute glucagon infusion consistently increased urinary sodium excretion and urine flow across all experimental groups, whereas renal blood flow did not change significantly. Urinary osmolality decreased in parallel with increased sodium and water excretion, and free water clearance remained negative despite increased urine flow, indicating solute-driven diuresis rather than antidiuretic hormone suppression. Receptor antagonist experiments demonstrated that blockade of either GCGR or GLP-1R partially attenuated the glucagon-induced renal responses. In conclusion, acute glucagon infusion induces natriuresis and diuresis primarily through a direct tubular mechanism, largely independent of renal hemodynamic changes. These effects are mediated by multiple overlapping receptor pathways, as neither GCGR nor GLP-1R blockade alone was sufficient to abolish the response, and their relative contributions may vary depending on physiological context. These findings may be relevant for understanding the renal effects of emerging glucagon-based therapies, including dual GLP-1/glucagon and triple GLP-1/glucose-dependent insulinotropic polypeptid (GIP)/glucagon receptor coagonists, where overlapping receptor activation could influence renal sodium handling.NEW & NOTEWORTHY Glucagon is best known for raising blood sugar, but what does it do to the kidneys? We show that glucagon consistently drives sodium and water excretion in rats through a direct tubular mechanism, largely independent of changes in renal blood flow. Neither glucagon receptor nor GLP-1 receptor blockade alone was sufficient to abolish the response, revealing overlapping receptor pathways. These findings have implications for the growing use of glucagon-based dual and triple agonist therapies.