Diurnal function of activating or inhibiting the vasopressin receptor 2 in the male and female mouse kidney

Renal function exhibits a circadian pattern including increased glomerular filtration rate, urine volume, and electrolyte excretion during the active period of humans and rodents. Water balance disorders, such as central diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion, affect the quality of life of these individuals. Current treatments involve the vasopressin receptor 2 (AVPR2) agonist, desmopressin (dDAVP) to promote water reabsorption, or the antagonist, tolvaptan, to promote diuresis. However, it is unclear if there is an optimal time of day to take these medicines to best prevent adverse events while being therapeutic. We hypothesized that the time of day may affect urine osmolality or flow in response to dDAVP or tolvaptan. Male and female C57BL/6J mice (10–11 wks, n= 6/group/sex) were studied. A week before dDAVP, the mice were placed on a high-water gel diet to suppress AVP and spot urine collected. The mice received a 10 μg i.p. injection of dDAVP at ZT5 (middle of inactive period) or ZT17 (middle of active period) and were euthanized one hour later (ZT6 and ZT18). For tolvaptan, the mice were kept on a standard pellet diet and were given a 0.5 mg i.p. injection at ZT6 and ZT18 and urine was collected hourly for five hours. In female dDAVP mice, urine osmolality rose similarly from 523.2 ± 147.1 to 2094.7 ± 543.3 mOsm/kg (4-fold) at ZT6 and from 583.4 ± 118.0 to 2454.0 ± 446.3 mOsm/kg (4.2-fold) at ZT18 (P time of day = 0.19, P dDAVP < 0.0001, P interaction = 0.35). Likewise in male mice in response to dDAVP urine osmolality at ZT6 increased from 845.8 ± 440.7 to 1749.2 ± 305.9 mOsm/kg (2.06-fold), while at ZT18 it increased from 1194.2 ± 328.8 to 1985.5 ± 298.1 mOsm/kg (1.66-fold) (P time of day = 0.056, P dDAVP < 0.0001, P interaction =0.71). However, plasma osmolality was significantly lower after dDAVP at ZT18 (284.0 ± 6.5 mOsm/kg) compared to ZT6 (294.0 ± 6.5 mOsm/kg) for the female mice and male mice (ZT18 = 290.2 ± 8.4 mOsm/kg, ZT6 = 297.0 ± 5.2 mOsm/kg) (P time of day = 0.0063, P sex = 0.11, P interaction = 0.55). This suggests that dDAVP led to significantly greater dilution of plasma during the active period. There were no significant diurnal patterns in aquaporin (AQP) abundance after dDAVP injection for AQP1, AQP2, AQP2 pS256 (activation site), AQP2 pS261 (inhibitory site), AQP3, and AQP4. However, females had greater AQP1 and AQP4 abundance compared to males at both times (P sex = 0.0016 and P sex < 0.0001, respectively), and AQP2 was greater in females at ZT18 (P interaction = 0.043). In response to tolvaptan, all mice urinated but there was no significant diurnal effect in urine volume or urine osmolality in both sexes. However, females produced less urine than males, especially in the first-hour post injection (female ZT6: 71.7 ± 77.4 µL, male ZT6: 787.3 ± 604.5 µL; female ZT18: 285.4 ± 360.2 µL, male ZT18: 551.3 ± 431.3 µL, P sex = 0.0006). These findings suggest that the effect of dDAVP is most significant when taken during the active period while tolvaptan was equally effective at promoting diuresis during the times tested. Sex differences in aquaporin abundance and drug potency highlight the importance of sex-specific approaches in water balance research and treatment. Intramural UAB funds and R01 DK128001 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.