Abstract
Background/Aims: We recently showed that the β<sub>3</sub>-adrenoreceptor (β<sub>3</sub>AR) is expressed in mouse kidney collecting ducts (CD) cells along with the type-2 vasopressin receptor (AVPR2). Interestingly, a single injection of a β<sub>3</sub>AR selective agonist promotes a potent antidiuretic effect in mice. Before considering the feasibility of chronic β<sub>3</sub>AR agonism to induce antidiuresis in vivo, we aimed to evaluate in vitro the signaling and desensitization profiles of human β<sub>3</sub>AR. Methods: Human β<sub>3</sub>AR desensitization was compared with that of human AVPR2 in cultured renal cells. Video imaging and FRET experiments were performed to dissect β<sub>3</sub>AR signaling under acute and chronic stimulation. Plasma membrane localization of β<sub>3</sub>AR, AVPR2 and AQP2 after agonist stimulation was studied by confocal microscopy. Receptors degradation was evaluated by Western blotting. Results: In renal cells acute stimulation with the selective β<sub>3</sub>AR agonist mirabegron, induced a dose-dependent increase in cAMP. Interestingly, chronic exposure to mirabegron promoted a significant increase of intracellular cAMP up to 12 hours. In addition, a slow and slight agonist-induced internalization and a delayed downregulation of β<sub>3</sub>AR was observed under chronic stimulation. Furthermore, chronic exposure to mirabegron promoted apical expression of AQP2 also up to 12 hours. Conversely, long-term stimulation of AVPR2 with dDAVP showed short-lasting receptor signaling, rapid internalization and downregulation and apical AQP2 expression for no longer than 3 h. Conclusions: Overall, we conclude that β<sub>3</sub>AR is less prone than AVPR2 to agonist-induced desensitization in renal collecting duct epithelial cells, showing sustained cAMP production, preserved membrane localization and delayed degradation after 12 hours agonist exposure. These results may be important for the potential use of chronic pharmacological stimulation of β<sub>3</sub>AR to promote antidiuresis overcoming in vivo renal concentrating defects caused by inactivating mutations of the AVPR2.
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