Abstract: FR-PO590

Long-Term Empagliflozin Administration Downregulates Aquaporin 2 despite the Increased Expression of V2 Vasopressin Receptor in Diabetic Rat Kidneys

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Chung, Sungjin, Vanderbilt University School of Medicine, Nashville, United States
  • Li, Zhilian, Vanderbilt University School of Medicine, Nashville, United States
  • Kim, Soojeong, 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)
  • Yang, Chul Woo, 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)
  • Koh, Eun Sil, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
Background

Beyond glucose lowering effect, it has been suggested that one of the possible mechanisms by which empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, provides the remarkable cardiovascular and renal protection observed in a recent trial may relate to its effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors is transient, and long-term data related to diuretic change are sparse.

Methods

This experiment assessed the effects of 12-week treatment with empagliflozin (3 mg/kg) on renal tubular function, related sodium transporters and water channels in diabetic OLETF rats by comparing it with other antihyperglycemic agents such as 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, serum sodium and potassium and fractional excretion of sodium did not significantly differ between empagliflozin-treated and control diabetic rats. Empagliflozin-treated diabetic rats produced slightly decreased but still high urine volume and glycosuria, and they showed significantly higher electrolyte-free water clearance than lixisenatide- or voglibose-treated diabetic rats. In empagliflozin-treated rats, renal protein expression of Na+-K+-2Cl- cotransporter (NKCC2), Na+/H+ exchanger isoform 3 (NHE3) and γ-epithelial Na+ channel (ENaC) were decreased, and Na+-Cl- cotransporter (NCC) and α-ENaC expressions were unaltered compared with control diabetic rats. Empagliflozin increased the expressions of aquaporin (AQP)-3 and AQP7 but did not affect AQP1 protein expression in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor (V2R), protein and mRNA levels of AQP2 in kidneys of empagliflozin-treated diabetic rats were significantly decreased than those of control diabetic rats. These were not observed in lixisenatide or voglibose-treated diabetic rats.

Conclusion

Taken together, longer use of empagliflozin may downregulate AQP2 expression regardless of the V2R activation by as-yet unidentified signaling pathways, contributing, in part, to polyuria in diabetic rats.

Funding

  • Government Support - Non-U.S.