Effects of Ovariectomy and Elastin Haploinsufficiency on Vasopressin Receptor-mediated Water Handling by the Kidney

The vasopressin system regulates urine volume by facilitating water reabsorption in the distal nephron upon stimulation of vasopressin V 2 receptors (V 2 R) localized on the basolateral membrane of principal cells of the distal nephron. Previously, we observed that elastin haploinsufficiency ( Eln +/- ) decreased urine volume and increased osmolality in female mice. Here, we examined how Eln +/- influences the vasopressin system to increase water reabsorption, thereby decreasing urine volume. To this end, adult male and female (sham or ovariectomized) wild type (WT) and Eln +/- male mice were acutely volume loaded by subcutaneous injection of 5% dextrose in normal saline (6% of body weight) immediately after intraperitoneal injection of vehicle (100 µl of 0.01% DMSO in normal saline), tolvaptan (1, 2, or 3 mg/kg), or the V 2 R agonist 1-deamino-8D-arginine vasopressin (dDAVP, 0.02, 0.06, or 0.2 µg/kg). Tolvaptan increased urine flow rate (UV·) at all doses in WT male mice (saline: 0.195±0.032 vs. 1 mg/kg: 0.328±0.039; 2 mg/kg: 0.343±0.017; 3 mg/kg: 0.412±0.044 µl/min/g BW, p=0.038, p=0.036 and p=0.0008, respectively, vs. saline) and at 3 mg/kg in female mice (saline: 0.243±0.037 vs. 3 mg/kg: 0.395±0.028 µl/min/g BW, p=0.022), while Eln +/- abolished tolvaptan’s effect on UV· at all doses in male mice (saline: 0.215±0.039 vs. 1 mg/kg: 0.270±0.016; 2 mg/kg: 0.248±0.060; 3 mg/kg: 0.304±0.019 µl/min/g BW, p=0.969, p=0.997 and p=0.609 respectively, vs. saline). In contrast, ovariectomy (OVX) had no effect on tolvaptan-induced polyuria in female mice. However, dDAVP injection caused a marked decrease in UV· at all doses in WT male mice (saline: 0.333±0.036 vs. 0.02 ug/kg: 0.222±0.028; 0.06 ug/kg: 0.178±0.028; 0.2 ug/kg: 0.030±0.019 µl/min/g BW, p=0.026, p=0.0198 and p=0.0017, respectively, vs. saline) but had no effect in Eln +/- male and sham female WT mice. In WT-OVX mice, dDAVP caused a robust decrease in UV· at 0.2 µg/kg (saline: 0.207±0.039 vs. 0.2 ug/kg: 0.048±0.009 µl/min/g BW, p=0.0102). Finally, tolvaptan had no effect on urine osmolality (U osm ) in female and Eln +/- mice but decreased U osm in WT males (saline: 617±95 vs. 1 mg/kg: 279±52; 3 mg/kg: 273±32 mmol/kg, p=0.0002 and p=0.0005 respectively, vs saline). In contrast, dDAVP increased U osm at all doses in Eln +/- male mice relative to saline-treated group (saline: 464±61 vs. 0.02 ug/kg: 1313±331; 0.06 ug/kg: 1822±108; 0.2 ug/kg: 1745±162 mmol/kg, p=0.0092, p<0.0001 and p<0.0001, respectively, vs. saline). Taken together, we conclude that Eln +/- and OVX enhance V 2 R-mediated renal tubular water reabsorption. NIH R01 HL174004-01A1, R56 DK132859-01A1 and R01 HL139754, Craig H. Neilsen Foundation Grant 382566, and Startup Funds from CWRU-SOM to Patrick Osei-Owusu. 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.