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Our data demonstrate that, in hyperhydrated rats, exenatide can promote recovery of water impermeability of the collecting ducts mediated by the secretion of PGE2 in the kidney. Thus, the effect of exenatide on PGE2 excretion depends on water balance. A similar situation is observed for the hypoglycaemic effect of GLP-1 and exenatide, because Protein Tyrosine Kinase inhibitor their effects on pancreatic insulin secretion depend on plasma glucose concentrations.[37] A recent study[38] with gene knockout mice indicated that the acute natriuretic effect of exenatide is mediated via the GLP-1 receptor. Our data suggest that exenatide affects renal water transport by acting as an agonist of the GLP-1 receptor. The present study demonstrated that an antagonist of the GLP-1 receptor weakened the hydrouretic effect of exenatide and decreased solute-free water excretion in water-loaded rats. Recently, it was shown that GLP-1 reproduced the hydrouretic effect of exenatide in hyperhydrated rats.[39] An increase of urinary cAMP excretion was observed when a high dose of exenatide (1.5?nmol/kg) was injected. These experimental results are consistent with data on the GLP-1 receptor (G-protein-coupled receptor with cAMP as a second messenger)[5] and its renal distribution. The GLP-1 receptor protein was detected in the kidney cortex, predominantly in the proximal Alectinib manufacturer tubular cells[5] and in renal blood vessels.[40] The mechanism of the hydrouretic effect of exenatide is complex and multicomponent. At present, we propose that there are at least two main components in the mechanism of exenatide-induced solute-free water formation: (i) an increase in distal tubular delivery and fluid influx to the collecting ducts due to inhibition of proximal sodium reabsorption; and (ii) acceleration of recovery of collecting duct water impermeability due to stimulation of PGE2 secretion. The hydrouretic effect of exenatide also depends on AVP-regulated collecting duct water permeability. Exenatide-induced renal GPX4 PGE2 secretion and plasma AVP levels depend on the degree of hydration and specify the physiological appropriateness of the hydrouretic response to a GLP-1 mimetic. In contrast with a V2 receptor antagonist, exenatide does not accelerate solute-free water excretion when there is no excess water in the organism. The data obtained are important not only for renal physiology but, presumably, they are also of particular clinical importance. Facilitation of solute-free water excretion in patients with hypo-osmia may be useful for the correction of this impairment. The authors would like to acknowledge Professor Mikhail I Titov and Mrs Sofia K Nikolskaya (Faculty of Chemistry of St Petersburg State University) for the synthesis of exenatide and the GLP-1 receptor antagonist. The authors also thank Editage (http://www.editage.com) for the English language editing of the paper.
