Scientific evidence for Kampo medicine's effects on regulating body ions and fluids — Akita University reveals mechanism for reducing edema

Swelling in the legs can occur due to excessive drinking, lack of exercise, or maintaining the same posture for extended periods, such as during airplane flights. Chronic edema causes leg heaviness and decreased physical strength, and also affects appearance, leading to reduced quality of life (QOL).

Known causes of edema include cell swelling and disruption of the ion balance surrounding cells, which affects fluid retention in tissues. While the Kampo medicine Boi-ogi-to has been recognized as effective for improving edema, the specific mechanisms of how it regulates ions at the cellular level to restore ion balance had not been fully elucidated.

A research group led by Lecturer Kaori Sato-Numata at the Graduate School of Medicine, Akita University, along with Medical Student Taro Suzuki (sixth year) and Professor Tomohiro Numata, has discovered a new mechanism by which the volume-sensitive outward rectifier (VSOR) anion channel in kidney cells transports chloride ions into the bloodstream, drawing excess fluid from tissues into the blood to reduce edema. This world-first discovery was published in The FASEB Journal.

VSOR is an ion channel involved in cell volume regulation, activated when cells swell to regulate cell volume and ion concentration by promoting the movement of chloride ions and water. Its core molecule, LRRC8A, forms complexes with other LRRC8 family proteins (LRRC8B-E) to carry out VSOR's functions.

The research group examined clinical data from patients taking Boi-ogi-to, focusing on changes in blood components, particularly chloride, potassium, and sodium. They found that blood chloride concentrations increased 3-5 weeks after starting the medication.

Next, they demonstrated that Boi-ogi-to treatment in human kidney cell lines and mouse isolated renal tubular cells caused chloride ions and accompanying water to move out of cells, resulting in cell shrinkage. By using inhibitors of the VSOR chloride ion channel, they showed that when this chloride outflow pathway was blocked, cell shrinkage was suppressed. This pharmacologically demonstrated that VSOR is the chloride outflow pathway (molecularly composed of LRRC8-containing molecules).

The group also conducted electrophysiological measurement (patch-clamp method) analysis. In human kidney cell lines and mouse isolated renal tubular cells, Boi-ogi-to-induced VSOR currents disappeared in cells with VSOR knockdown using siRNA. When LRRC8A/8C, molecules thought to constitute VSOR, were reconstituted in LRRC8 family-deficient cells, Kampo medicine-induced VSOR currents could be recorded upon treatment.

To observe LRRC8A behavior, they expressed LRRC8A molecules with attached GFP fluorescence in cells and monitored molecular behavior during Boi-ogi-to treatment. They discovered that upon applying Boi-ogi-to, LRRC8A relocated from the cytoplasm to the cell membrane. This demonstrated a unique activation mechanism where Kampo medicine causes LRRC8A molecules to move to the cell membrane to function as chloride ion channels.

This research revealed that Boi-ogi-to may improve edema by promoting chloride ion transport in kidney cells and regulating body ions and fluids. It adds scientific support to the empirically known effects of Kampo medicine. These findings provide new insights into the importance of ion balance regulation in edema treatment and are expected to contribute to establishing scientific evidence for edema treatment using Kampo medicine and developing more effective treatment strategies.

Numata has demonstrated scientific evidence for other Kampo medicines as well. He states, "In basic research assignments, we allow students to choose Kampo medicines they're interested in and pursue research. Students choose based on reasons such as medicines used by family members or themselves, wondering why they work. This provides strong motivation and makes for good research subjects. Personally, I hope that by researching Kampo medicines with recognized effects, more people can use them confidently for prevention and treatment based on scientific evidence. At the same time, I hope to use Kampo medicines as a tool to clarify physiological mechanisms."

Journal Information
Publication: The FASEB Journal
Title: Boi-Ogi-To, a Traditional Japanese Kampo Medicine, Promotes Cellular Excretion of Chloride and Water by Activating Volume-Sensitive Outwardly Rectifying Anion Channels
DOI: 10.1096/fj.202403278R