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Abstract: TH-PO502

Empagliflozin Contributes to Polyuria via Transcriptional and Post-translational Control of Aquaporin-2 in Diabetic Rat Kidneys

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Chung, Sungjin, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Shin, Seok Joon, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yong-Soo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Yang, Chul Woo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Koh, Eun Sil, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
Background

It has been suggested that one of the most possible mechanisms for the positive cardiovascular and renal outcomes observed with empagliflozin, a selective sodium-glucose contransporter type 2 (SGLT2) inhibitor, would be related to effects on osmotic diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse.

Methods

This study investigated the effect of a 12-week treatment with empagliflozin (3 mg/kg) on renal sodium transporters and water channels in diabetic OLETF rats by comparing it with other antihyperglycemic agents that included lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor.

Results

At 12 weeks of treatment, the serum sodium level and fractional excretion of sodium were not significantly different between empagliflozin-treated and control diabetic rats. Empagliflozin-treated diabetic rats produced slightly decreased, but still high, urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than diabetic rats treated with other agents. In empagliflozin-treated rats, renal protein expressions of Na+-K+-2Cl- cotransporter and epithelial Na+ channel were decreased, and Na+-Cl- cotransporter expression was unaltered compared with control diabetic rats. Empagliflozin increased the expression of aquaporin (AQP)7 but did not affect AQP1 and AQP3 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in kidneys of empagliflozin-treated diabetic rats were significantly decreased compared to control diabetic rats. In addition, empagliflozin increased the phosphorylation of AQP2 at S261 through the activation of p38- mitogen-activated protein kinase, protein phosphatase 2B and glycogen synthase kinase 3α, and cyclin-dependent kinases 1 and 5.

Conclusion

The collective results indicate that the long-term use of empagliflozin may promote diuresis associated with downregulation of AQP2 as well as its sustained natriuretic ability.

Funding

  • Government Support - Non-U.S.