Among micronutrient minerals, sodium has gotten a lot of attention. It is generally understood that eating too much salt raises blood pressure and can cause cardiovascular problems. But consuming too little of the mineral potassium can cause similar cardiovascular issues.
“High sodium is bad; low potassium is bad; and the combination is particularly bad. And it just so happens that the diet we consume in the U.S. on a population level is very high in sodium and low in potassium,” said Andrew Terker, MD, PhD, assistant professor of Medicine in the Division of Nephrology and Hypertension.
Now, Terker and a multidisciplinary research team have identified a protein in the kidney that responds to low levels of blood potassium and the signaling pathways that it uses to change kidney function. Their findings, published in the journal Nature Communications, suggest that the protein — a potassium channel called Kir4.2 — may be a target for new therapeutics to treat kidney disease, high blood pressure and other cardiovascular diseases.
Terker and his colleagues focused on the proximal tubule segment of the kidney, which constitutes the bulk of kidney mass and is the main area for moving sodium and potassium from urine back into the blood (reabsorption).
They suspected a role for Kir4.2, which regulates the movement of potassium ions across kidney cell membranes. In studies in mouse models and isolated kidney tubules, they demonstrated that Kir4.2 responds to low blood potassium by activating sodium reabsorption pathways, protein production and cell growth pathways.
“In response to low potassium, Kir4.2 ‘turns on’ the proximal tubule cell and revs up its function, putting the proximal tubule and the whole kidney in general into overdrive,” said Terker, the senior and corresponding author of the new study. “We’re trying to understand what this metabolic overdrive is doing to kidney cells and to whole body physiology.”
In previous work, Terker and his colleagues showed that genetic deletion of the Kir4.2 channel protected mice from low potassium-related kidney injury, supporting the potential of therapeutics that block this protein to treat kidney diseases, and potentially cardiovascular diseases like high blood pressure.
In the potassium homeostasis field, the kidney proximal tubule has been a relatively understudied region of the kidney, Terker said.
“We see the proximal tubule as having a lot of potential therapeutic targets — this family of potassium channels and the downstream pathways they influence being some of them — that we have yet to take advantage of for treating disease,” he said.
About 37 million Americans (more than 1 in 7 adults) have chronic kidney disease, according to the National Institute of Diabetes and Digestive and Kidney Diseases.
Another outcome Terker hopes will come from his team’s studies is an understanding of how much dietary potassium is optimal for health.
“We’re still trying to figure out the right amount of dietary potassium,” he said. “When people ask me — ‘What should I be eating?’ — I advise avoiding processed foods, because processing generally adds sodium and removes potassium, but ideally, our work will help define the healthiest amount of dietary potassium.”
Co-authors of the study include Yahua Zhang, MD, Fabian Bock, J.P. Arroyo, MD, PhD, Ming-Zhi Zhang, MD, and Raymond Harris, MD, in the Division of Nephrology and Hypertension at VUMC; Mohammed Ferdaus, PhD, Jerod Denton, PhD, and Eric Delpire, PhD, in the Department of Anesthesiology at VUMC; Kristie Rose, PhD, and Purvi Patel, MS, in the Mass Spectrometry Research Center at Vanderbilt University; and Alan Weinstein, MD, at Weill Cornell Medicine in New York.
The research was supported by the National Institutes of Health (grants DP5OD033412, R01DK051265, R01DK095785, R01DK062794, T32DK007569, P30DK114809, K08DK135931), Department of Veterans Affairs, Vanderbilt Center for Kidney Disease, Vanderbilt Diabetes Research and Training Center, American Heart Association, American Society of Nephrology, and a Vanderbilt Faculty Research Scholars Award.
