Potassium and Its Role in Hypertension and Chronic Kidney Disease

In the mass media and the layperson’s press, a high sodium diet garners the most attention with respect to its contribution to hypertension, heart disease, and kidney health. The media forgets to mention the critical importance of dietary potassium. Research has shown that increasing dietary potassium, despite high sodium intake, is sufficient to reduce blood pressure and can protect against heart disease and chronic kidney disease.

 For Cary Boyd-Shiwarski, MD, PhD, an assistant professor of medicine in the Renal-Electrolyte Division, it is all about potassium and its role in kidney health and function. Dr. Boyd-Shiwarski joined the Division as a faculty member in 2016 after completing her renal-electrolyte fellowship in the Division, in addition to completing both her medical degree and residency at the University of Pittsburgh School of Medicine.

 What drives the majority of Dr. Boyd-Shiwarski’s research is the fundamental importance of one’s diet to blood pressure and renal health and function. Clinically, Dr. Boyd-Shiwarski is most interested in the management of hypertension and chronic kidney disease (CKD), and she also has an active practice caring for patients with inherited conditions that can drive electrolyte imbalances and CKD, such as Fabry disease, Gitelman syndrome, and Alport syndrome.

 Dr. Boyd-Shiwarski’s research interests generally revolve around potassium homeostasis and ion transport, with a focus on the regulation of the thiazide-sensitive sodium-chloride cotransporter, NCC, by WNK (With-No-Lysine) kinases. Activating mutations to WNK kinases are known to cause hypertension and hyperkalemia in humans, through activation of NCC. These patients are exquisitely sensitive to treatment with thiazide diuretics. Some of Dr. Boyd-Shiwarski’s recent studies have focused on the role of a kidney-specific isoform of WNK1 to facilitate the formation of a protein complex in response to a low potassium diet.

 In 2018, Dr. Boyd-Shiwarski secured K08 funding from the National Institutes of Health to support her continuing research into a phenomenon specific to kidney function and potassium homeostasis known as WNK body formation

 The Importance of Potassium on Kidney Function and Health

For more than 100 years the importance of dietary potassium has been recognized for its ability to act as a diuretic and reduce blood pressure. Still, according to recent research, a full 98 percent of the United States population does not consume the recommended daily intake of this important element.

 “Because I’m interested at a fundamental level on what will keep the kidneys healthy, and how they function at the cellular and molecular levels, my research uses mouse models to study the effects of various types of potassium (e.g., potassium depletion, potassium citrate, potassium chloride) and their effect on hypertension, kidney function, and health,” says Dr. Boyd-Shiwarski.

 Her animal model experiments assess blood pressure, weight change, and serum levels of sodium and potassium with the long-term goal of determining how various diets and levels of potassium affect kidney function.

 The health of the kidney in relation to potassium intake also plays a role in Dr. Boyd-Shiwarski’s research. Her research assesses WNK kinases that regulate sodium transport in the kidney and how they are affected by varying levels of potassium intake relative to various overall dietary loading schemes to develop a better understanding of how a normal kidney responds to different potassium diets.

 “My new K08 grant is designed — at a general level — to investigate how the kidney senses potassium levels and then translate this information into blood pressure and kidney health. We think WNK kinases are one of the mechanisms by which the kidney senses potassium. These kinases sense changes in potassium levels and then coordinate volume and potassium homeostasis by regulating renal sodium transport,” says Dr. Boyd-Shiwarski.

 Her studies on this front involve knockout models that have a deletion for the KS-WNK1 kinase.

 “With manipulations to dietary potassium, and by varying the potassium anion with either citrate or chloride, we are determining how KS-WNK1 senses potassium and relays that message to downstream sodium transporters. Do the KS-WNK1 knock-out mice sense potassium differently? Is their blood pressure different in response to potassium? Do their kidneys show telltale signs of chronic kidney disease, or are they more resistant? This involves knowing what role these kinases play within the kidney,” says Dr. Boyd-Shiwarski.

 Dr. Boyd-Shiwarski’s research also entails studies to understand how the KS-WNK1 kinase functions in the distal convoluted tubule of the nephron, and how changes in that part of the nephron can affect the entire nephron — in the proximal tubule, the cortical collecting duct, and the loop of Henle.

 WNK Bodies and New K08 Research

Creatures — mice, humans — that exist for long periods on a low potassium diet have been found to form what is known as “WNK bodies” in the kidney. These WNK bodies are transient aggregates that form exclusively in the distal convoluted tubules.

 “We do not believe these bodies are pathological but are rather a kind of protective phenomenon that occurs when potassium levels are low for extended periods. They can form rapidly when potassium levels decrease substantially, but they also dissipate once normal levels are achieved,” says Dr. Boyd-Shiwarski.

 Researchers have known about the existence of these WNK bodies for over eight years, and that low levels of potassium in the diet lead to their formation, but until very recently, it was not known what molecular processes drove the formation. That is until Dr. Boyd-Shiwarski and colleagues published on the matter in 2017.¹ What Dr. Boyd-Shiwarski’s team found is that the KS-WNK1 kinase is responsible for their formation. The next question for Dr. Boyd-Shiwarski to answer is: Why do they form?

 “Why in a low potassium diet do these puncta form in the kidney? This also is a central part of the K08 grant. The first part of the K08 is designed to investigate further how potassium and potassium imbalance regulate blood pressure. The second aspect is understanding why WNK bodies form when potassium is low, and how they affect blood pressure. Our working hypothesis is that they regulate the sodium chloride cotransporter NCC, but we do not understand how … we are trying to assemble the full picture of this process whereby low dietary potassium occurs (i.e., the Western diet) and WNK bodies form that are KS-WNK1-dependent. Again, we believe they serve some form of protective role in the kidney to sense the potassium and then act downstream on the NCC cotransporter to regulate sodium reabsorption, which eventually affects blood pressure. I am excited about this research project because it is possible that we could reduce the burden of hypertension and chronic kidney disease by simply increasing dietary consumption of potassium. Given the significant burden of the two diseases, further research into effective measures to prevent hypertension and chronic kidney disease is needed,” says Dr. Boyd-Shiwarski.

 References

1 Boyd-Shiwarski CR, Shiwarski DJ, Roy A, Namboodiri HN, Nkashama LJ, Xie J, McClain KL, Marciszyn A, Kleyman TR, Tan RJ, Stolz DB, Puthenveedu MA, Huang CL, Subramanya AR.Potassium-regulated Distal Tubule WNK Bodies Are Kidney-specific WNK1 Dependent. Mol Biol Cell. 2018 Feb 15; 29(4): 499-509. Epub 2017 Dec 13.

 2 The Function of Kidney-Specific (KS)-WNK1 Condensates During Potassium Stress. NIH Project Number: 1K08DK118211-01.

 Further Reading

Ray EC, Boyd-Shiwarski CR, Kleyman TR. Why Diuretics Fail Failing Hearts. J Am Soc Nephrol. 2017 Nov; 28(11): 3137-3138. Epub 2017 Aug 18.

 Boyd-Shiwarski CR, Subramanya AR. The Renal Response to Potassium Stress: Integrating Past With Present. Curr Opin Nephrol Hypertens. 2017 Sep; 26(5): 411-418. Review.