Potassium Homeostasis, Chronic Kidney Disease, and the Plant-Enriched Diets

There are data demonstrating that ingestion of potassium-rich foods reduces the incidence of stroke, hypertension, nephrolithiasis, and osteoporosis. Dietary-consumption data indicate Westernized diets are high in processed foods, high in sodium content, and low in potassium. In fact, there are data suggesting individuals are not consuming enough potassium in their diet. Although consumption of diets high in plant proteins, fruits, and vegetables—which are excellent sources of potassium—is recognized as healthy and beneficial, individuals with decrements in their kidney function have been advised to avoid these foods. In reviewing the literature that provides the rationale for potassium restriction in patients with reductions in kidney function, it appears there is little direct evidence to support the levels of restriction which are now prescribed. Additionally, there are two new potassium-binding agents which are well tolerated and have been documented to be effective in controlling serum potassium. Therefore, with the new binding agents and the lack of empirical evidence supporting the stringent dietary potassium restrictions, the authors conclude by indicating the pressing need for further research focusing on dietary liberalization of potassium in patients with reductions in kidney function to enhance overall health and well being, to provide them cardiovascular benefits, and to reduce overall risk of mortality through the incorporation of potassium-enriched foods.

WNK4 kinase is a physiological intracellular chloride sensor

With-no-lysine (WNK) kinases regulate renal sodium-chloride cotransporter (NCC) to maintain body sodium and potassium homeostasis. Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII). X-ray crystal structure and in vitro studies reveal chloride ion (Cl−) binds to a hydrophobic pocket within the kinase domain of WNKs to inhibit its activity. The mechanism is thought to be important for physiological regulation of NCC by extracellular potassium. To test the hypothesis that WNK4 senses the intracellular concentration of Cl−physiologically, we generated knockin mice carrying Cl−-insensitive mutant WNK4. These mice displayed hypertension, hyperkalemia, hyperactive NCC, and other features fully recapitulating human and mouse models of PHAII caused by gain-of-function WNK4. Lowering plasma potassium levels by dietary potassium restriction increased NCC activity in wild-type, but not in knockin, mice. NCC activity in knockin mice can be further enhanced by the administration of norepinephrine, a known activator of NCC. Raising plasma potassium by oral gavage of potassium inactivated NCC within 1 hour in wild-type mice, but had no effect in knockin mice. The results provide compelling support for the notion that WNK4 is a bona fide physiological intracellular Cl−sensor and that Cl−regulation of WNK4 underlies the mechanism of regulation of NCC by extracellular potassium.