Kidney Week

Abstract: SA-PO1013

Metformin Has Natriuretic Effects Through Reduction of the Sodium-Chloride Cotransporter Phosphorylation

Session Information

• Fluid and Electrolytes: Basic - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Hashimoto, Hiroko, Tokyo Medical and Dental University, Tokyo, Japan

Hiroko Hashimoto,

• Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Japan

Naohiro Nomura,

• Shoda, Wakana, Tokyo Medical and Dental University, Tokyo, Japan

Wakana Shoda,

• Isobe, Kiyoshi, Tokyo Medical and Dental University, Tokyo, Japan

Kiyoshi Isobe,

• Kikuchi, Hiroaki, Tokyo Medical and Dental University, Tokyo, Japan

Hiroaki Kikuchi,

• Yamamoto, Kohei, Tokyo Medical and Dental University, Tokyo, Japan

Kohei Yamamoto,

• Fujimaru, Takuya, Tokyo Medical and Dental University, Tokyo, Japan

Takuya Fujimaru,

• Ando, Fumiaki, Tokyo Medical and Dental University, Tokyo, Japan

Fumiaki Ando,

• Mori, Takayasu, Tokyo Medical and Dental University, Tokyo, Japan

Takayasu Mori,

• Okado, Tomokazu, Tokyo Medical and Dental University, Tokyo, Japan

Tomokazu Okado,

• Rai, Tatemitsu, Tokyo Medical and Dental University, Tokyo, Japan

Tatemitsu Rai,

• Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Japan

Shinichi Uchida,

• Sohara, Eisei, Tokyo Medical and Dental University, Tokyo, Japan

Eisei Sohara,

Background

Metformin is an antidiabetic drug that is widely used to treat patients with type 2 diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys.

Methods

We firstly examined urinary sodium excretion and expression of renal sodium transporters in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin. In addition, we examined metformin effects using ex vivo preparations of mice kidney slices. We also performed experiments using the spontaneously hypertensive rat (SHR).

Results

In this study, we demonstrated that metformin increased urinary sodium excretion by reducing phosphorylation of the thiazide-sensitive Na-Cl cotransporter (NCC) in acute and chronic metformin administration. We also confirmed reduction of phosphorylated NCC in an ex vivo study. Expression levels of other renal sodium transporters, such as NKCC2, ENaC, and NHE3 did not show significant changes. WNK-OSR1/SPAK kinase signal was not involved in this effect of metformin on NCC. We finally performed experiments using SHR, whose blood pressure is well known to be decreased by metformin. We observed decreased phosphorylated NCC in SHR by metformin treatment, suggesting that this decreased NCC phosphorylation is involved in the mechanisms of metformin-induced blood pressure reduction.

Conclusion

Metformin increased urinary sodium excretion by reducing phosphorylation of NCC. Considering that metformin could have natriuresis effect, metformin could be an ideal drug for excessive salt intake, in addition to excessive calorie intake.

Funding

• Government Support - Non-U.S.