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Abstract: TH-PO490

Osmotic Diuresis by SGLT2 Inhibition Is Associated with Increased Renal Solute-Free Water Reabsorption and AQP2 Expression in Diabetic Rats

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Masuda, Takahiro, Jichi Medical University, Shimotsuke, Japan
  • Muto, Shigeaki, Jichi Medical University, Shimotsuke, Japan
  • Fukuda, Keiko, Jichi Medical Universtiy, Shimotsuke, Japan
  • Watanabe, Minami, Jichi Medical Universtiy, Shimotsuke, Japan
  • Watanabe, Yuko, Jichi Medical University, Shimotsuke, Japan
  • Ohara, Ken, Jichi Medical University, Shimotsuke, Japan
  • Koepsell, Hermann, University of Würzburg, Germany, Würzburg, Germany
  • Maeshima, Akito, Jichi Medical University, Shimotsuke, Japan
  • Vallon, Volker, University of California San Diego, San Diego, California, United States
  • Nagata, Daisuke, Jichi Medical University, Shimotsuke, Japan
Background

Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium-glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is associated with a sustained diuretic and natriuretic tone that activates compensatory increases in fluid and food intake to stabilize body fluid volume (Am J Physiol Renal Physiol 2018, May 23. doi: 10.1152/ajprenal.00143.2018). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear.

Methods

Non-obese type 2 diabetic Goto-Kakizaki (GK) rats were treated with vehicle (Veh) or 0.01% (in diet) ipragliflozin (Ipra) (n= 4-5) with free access to food and water. After 8 weeks, GK rats were placed in metabolic cages for 24h urine collection. Blood was collected by cardiac puncture and whole kidneys for western blot were harvested under terminal isoflurane anesthesia.

Results

Body weight (365±10 vs. 353±5 g) and serum glucose (303±46 vs. 312±25 mg/dL) were similar between Veh and Ipra. Ipragliflozin increased food and fluid intake (food: 19.5±1.5 vs. 27.8±0.9 g/24h*, fluid: 37.0±7.0 vs. 87.0±5.9 mL/24h*, *P<0.05 vs Veh), urine volume (25.7±3.9 vs. 64.2±4.9 mL/24h*), urinary glucose excretion (1.0±0.6 vs. 5.9±0.4 g/24h*), urinary Na+ excretion (2.2±0.2 vs. 3.2±0.3 mEq/24h*), renal osmolar clearance (128±17 vs. 265±13 mL/24h*) and solute-free water reabsorption (102±14 vs. 201±9 mL/24h*). The renal membrane protein expression of SGLT2 and AQP2 was increased, whereas NKCC2 expression was decreased in the Ipra vs Veh group. The expression of SGLT1, NHE3, phosphorylated NHE3 (S605 and S552), AQP1 and ENaC (aENaC, bENaC and gENaC) was similar between the groups.

Conclusion

The SGLT2 inhibitor ipragliflozin induced a sustained glycosuria, diuresis, and natriuresis, and increased solute-free water reabsorption in the kidneys of diabetic rats. The latter was associated with an increase in renal AQP2 expression. These results suggest that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid reabsorption in the collecting duct.

Funding

  • Government Support - Non-U.S.