Abstract: TH-PO0038
Diuretic Effect of Urea Transporter-A1 Inhibition in Aldosterone-Treated Mice
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Kuma, Akihiro, Hyogo Medical University, Department of Cardiovascular and Renal Medicine, Nishinomiya, Japan
- Matsuzaki, Mitsunori, Hyogo Medical University, Department of Cardiovascular and Renal Medicine, Nishinomiya, Japan
- Sands, Jeff M., Emory University, Atlanta, Georgia, United States
- Nanami, Masayoshi, Hyogo Medical University, Department of Cardiovascular and Renal Medicine, Nishinomiya, Japan
- Maeda, Kiyo, Hyogo Medical University, Department of Cardiovascular and Renal Medicine, Nishinomiya, Japan
- Kuragano, Takahiro, Hyogo Medical University, Department of Cardiovascular and Renal Medicine, Nishinomiya, Japan
Background
In chronic kidney disease (CKD), serum aldosterone level is high, which induces fluid and sodium retention. Diuretics are commonly used to treat those conditions. Urea plays a critical role in urinary concentrating mechanism and in maintenance of water balance. We showed that inhibition of urea transporter (UT)-A1 caused diuresis in CKD mice due to 5/6 nephrectomy. Here, we investigated physiological changes for fluid retention by UT-A1 inhibition in aldosterone-treated mice.
Methods
Mice (C57BL/6J) were fed with an 8% NaCl diet for 4 wks to produce fluid and sodium retention. Aldosterone (Aldo, 0.2 μg/kg/min.) was administrated by implanting osmotic mini-pumps. Dimethylthiourea (DMTU, 100 mg/kg/day), a UT-A1 inhibitor, or furosemide (15 mg/kg/day) was administrated by intraperitoneal injection. Daily urine was collected in metabolic cages. Blood pressure (BP) was measured by tail-cuff. Mice were initially divided into three groups (control: Ctrl, Aldo-vehicle: Aldo-v, and Aldo-DMTU: Aldo-D). Then mice were divided into two groups (Aldo-D and Aldo-furosemide: Aldo-F) to compare the effect of the two diuretics.
Results
In Aldo-D mice, 24-hr urine volume corrected by body weight was greatest among three groups; 0.31 mL/g (Ctrl), 0.71 mL/g (Aldo-v), and 1.16 mL/g (Aldo-D) (P <0.0001). Urine osmolality was lowest in Aldo-D mice (P <0.0001). Daily Na excretion in Aldo-D was larger than in Aldo-v (3.63 mEq/day vs 4.84 mEq/day), but did not significantly. Systolic BP in Aldo-v mice increased compared with Ctrl mice (93 mmHg vs 108 mmHg, P = 0.003). However, DMTU decreased systolic BP during Aldo stimulation (Aldo-D; 84 mmHg, P <0.001 vs Aldo-v). Therefore, DMTU may suppress fluid and sodium retention due to Aldo stimulation. In addition, Aldo stimulation increased heart-to-body weight (4.60 mg/g (Ctrl) vs 5.18 mg/g (Aldo-v); P = 0.006), and DMTU ameliorated heart hypertrophy (4.49 mg/g, P = 0.001 vs Aldo-v). Comparing DMTU to furosemide, DMTU increased 24-hr urine volume (1.11 mL/g (Aldo-D) vs 0.82 mL/g (Aldo-F), P = 0.11). Fractional excretion of Na was significantly higher in Aldo-F, but in Aldo-D, daily Na excretion was higher (4.53 mEq/day (Aldo-D) vs 3.56 mEq/day (Aldo-F), P = 0.20).
Conclusion
UT-A1 inhibition may reduce fluid and sodium retention, even when mice are stimulated by aldosterone. A UT-A1 inhibitor may be an attractive diuretic for overfilling conditions.