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Abstract: FR-PO618

Role of Vasopressin V2 Receptor Signaling in NKCC2 Regulation in Diabetes Mellitus

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Sakai, Kazuhiro, Teikyo University, Tokyo, Japan
  • Yamazaki, Osamu, Teikyo University, Tokyo, Japan
  • Ishizawa, Kenichi, Teikyo University, Tokyo, Japan
  • Nemoto, Yoshikazu, Teikyo University, Tokyo, Japan
  • Fujigaki, Yoshihide, Teikyo University, Tokyo, Japan
  • Shibata, Shigeru, Teikyo University, Tokyo, Japan
Background

Previous studies have reported that vasopressin V2 receptor is present in thick ascending limb (TAL) of loop of Henle and can regulate the abundance of Na-K-2Cl cotransporter (NKCC2). Nonetheless, the upstream signaling and the pathological significance in a disease state remains obscure. We aimed to address the role of vasopressin V2 signaling in TAL in diabetic kidney disease.

Methods

We compared the levels of aquaporin 2 and NKCC2 in the membrane fraction of the kidney between db/+ and db/db mice. We then orally administered tolvaptan, vasopressin V2 receptor antagonist, to db/+ and db/db mice for two weeks and evaluated the changes in aquaporin 2 and NKCC2. To test the role of V2 signaling in humans, we obtained urinary exosomes from diabetic subjects treated with tolvaptan and compared the levels of aquaporin 2 and NKCC2 before and after the treatment.

Results

The administration of tolvaptan reduced aquaporin 2 abundance in db/+ mice. We also found that NKCC2 abundance was reduced by tolvaptan in this model. To evaluate the role of vasopressin signaling in diabetic kidney, we compared their levels between db/+ and db/db mice, and found that both aquaporin 2 and NKCC2 were significantly elevated in db/db mice (1.87-fold increase for aquaporin 2; P = 0.03, and 1.90-fold increase for NKCC2; P<0.001). Moreover, these levels were significantly reduced by tolvaptan administration, indicating the contribution of vasopressin V2 signaling in the kidney in db/db mice. To extend these observations into humans, we evaluated NKCC2 levels in urinary vesicles in subjects with diabetic kidney disease who received tolvaptan. Among 15 subjects examined, six showed response to tolvaptan, resulting in reduced aquaporin 2 levels in urinary exosome. In these cases, NKCC2 levels tended to reduce after the treatment.

Conclusion

Vasopressin V2 receptor signaling is involved in the regulation of NKCC2, which can be dysregulated in the kidney of diabetes mellitus.