Renal function in humans and rodents displays a clear circadian pattern with greater glomerular filtration and excretion during the active period. Vasopressin (AVP) regulates water balance primarily through the vasopressin receptor 2 (V2R). Although both V2R agonists and antagonists are used clinically, it remains unclear whether their efficacy vary by the time of day. Because Avpr2 mRNA expression is greater during the active phase in mice, we hypothesized that V2R agonism and antagonism would produce diurnal effects on urine-concentrating responses. Adult male and female C57BL/6J mice were studied. To suppress endogenous AVP, mice were placed on a high-water gel diet one week before a 10 μg intraperitoneal injection of dDAVP at ZT5 or ZT17 and then samples collected one hour later. dDAVP administered during the active period resulted in a more diluted plasma, reflected by lower plasma osmolality at ZT18. This response associated with increased abundance of AQP2 phosphorylated at S256 and S261 in the outer medulla of the ZT18 mice compared to the ZT6 mice. Thus, dDAVP is more effective during the active period when water intake is greatest and there is enhanced renal filtration and reabsorptive capacity. Conversely, when the V2R was inhibited by tolvaptan, urine flow peaked 2 hours post the injection in the male and female mice, regardless of it was ZT18 or ZT6. However, male mice produced significantly more urine than the female mice in response to the tolvaptan. In conclusion, both time of day and sex significantly influenced renal responses to V2R-targeted therapies.
Nguyen et al. (Thu,) studied this question.