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Abstract: FR-PO613

Tacrolimus Improved Symptoms of Type 4 Bartter Syndrome Model Mice

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Matsuura, Yoshiaki, Tokyo Medical and Dental University, Tokyo, Japan
  • Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Japan
  • Shoda, Wakana, Tokyo Medical and Dental University, Tokyo, Japan
  • Sohara, Eisei, Tokyo Medical and Dental University, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Medical and Dental University, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Japan

Group or Team Name

  • Department of Nephrology
Background

Type 4 Bartter syndrome (BS) is a hereditary tubular disease characterized by salt-losing polyuria, hypokalemia, and metabolic alkalosis. Because barttin (coded by Bsnd gene, which is a disease causing gene of type 4 BS) is expressing from thick ascending limbs of Henle’s (TAL) to collecting ducts, the function of distal nephron is widely impaired and the symptoms of type 4 BS are generally very severe. Although potassium replacement therapy has been mainly used for hypokalemia, there is no fundamental treatment for type 4 BS. It has been reported that calcineurin inhibitors enhance phosphorylation of sodium (Na) -potassium (K) -2 chloride (Cl) cotransporter (NKCC2) and Na-Cl cotransporter (NCC), which are key sodium transporters in TAL and distal convoluted tubule, respectively. In this study, we hypothesized that tacrolimus, a calcineurin inhibitor, would increase in phosphorylation of NKCC2 and NCC, and improve symptoms of type 4 BS.

Methods

Bsndneo / neo mice, which is hypomorphic of barttin, were used as a model of type 4 BS. Bsndneo/neo showed severe polyuria, hypokalemia, and metabolic alkalosis. Tacrolimus was administered subcutaneously once a day. After a week administration of tacrolimus, blood sampling and kidney harvest were performed. Phosphorylation of NKCC2 and NCC was evaluated by Western blotting. For the investigation of urine volume and urinary K excretion, urine was collected in a urine collection cage after a single intraperitoneal administration of tacrolimus.

Results

After a week administration of tacrolimus, serum potassium levels were significantly increased in Bsndneo / neo mice. However, improvement of metabolic alkalosis was not observed after tacrolimus treatment. After single administration of tacrolimus, urinary K excretion was significantly reduced, and urine volume also tended to be decreased. Phosphorylation of NKCC2 and NCC was significantly increased in Bsndneo / neo mice.

Conclusion

Tacrolimus administration ameliorated hypokalemia in type 4 BS model mice by suppressing urinary K excretion. Increase in phosphorylation of NCC and NKCC2 would contribute to the improvement of hypokalemia in type 4 BS. Tacrolimus might be effective for the treatment of type 4 BS.

Funding

  • Government Support - Non-U.S.