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Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are two distinct types of antidepressants. Hyponatremia can occur with both SSRIs and SNRIs. We previously reported that SSRIs such as sertraline upregulate aquaporin-2 (AQP2) through accelerated AQP2 transcription. However, the mechanism by which serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine retain water in the kidney remains unknown. This study was conducted to investigate the mechanism through which duloxetine induces antidiuresis in lithium-induced nephrogenic diabetes insipidus (Li-NDI).
Two different animal experiments were carried out using male Sprague-Dawley rats to investigate the effects of duloxetine treatment in Li-NDI and to assess whether the results were reversed by co-administration of tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for a period of 2 weeks. Duloxetine (50 mg/kg/d) and tolvaptan (10 mg/kg/d) were additionally provided in the food for the same duration. At the end of each animal experiment, the kidneys were collected for the measurement of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2) levels.
Urine output was increased by lithium treatment and decreased by duloxetine co-treatment. Urine osmolality was decreased by lithium treatment and increased by duloxetine co-treatment. The abundances of AQP2 protein and mRNA were decreased by lithium treatment and restored by duloxetine cotreatment. Consistently, phosphorylation of CREB was decreased by lithium treatment and restored by duloxetine cotreatment. Notably, the expression of V2R mRNA was decreased by lithium treatment and restored by duloxetine cotreatment. In the subsequent experiment, the antidiuretic effect induced by duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also prevented the alterations in AQP2 and CREB-1 protein levels in the kidneys of Li-NDI rats. Reduced cAMP levels in the kidneys of Li-NDI rats were elevated by duloxetine treatment, and this effect was reversed by co-treatment with tolvaptan. However, the elevated levels of PGE2 in Li-NDI rat kidneys were not affected by either duloxetine treatment or tolvaptan co-treatment.
Duloxetine acts as a V2R agonist and can induce hyponatremia by stimulating the V2R-cAMP-AQP2 pathway in the kidney. Based on the results of our study, we propose tolvaptan as a promising therapy for drug-induced hyponatremia.
This abstract has been revised from the previous submission for the KSN 2023 (Seoul, Korea). By submitting the abstract to WCN’24, abstract authors declare that re-submitting the abstract is permitted by the organizers of the previous meeting.