Abstract
A potassium (K+) rich diet is known to have an antihypertensive effect that has been embodied by the NHLBI in the DASH diet. However, the molecular basis for this blood pressure‐lowering effect has been unclear, until a recent study proposed a model in which the DCT cells of the kidney regulate their salt transport in response to variations in intracellular chloride ([Cl−]i), which are directly regulated by serum K+. With the knowledge that WNK proteins are Cl− sensors, and are a part of the WNK/SPAK/NCC signaling cascade which regulates the NCC, the main salt transporter in the distal nephron, we examined the effect of serum K+ on the ([Cl−]i) and, in turn its effect on the WNK4 signaling pathway in a “modified HEK 293T” cell line. Using a fluorescence‐based approach in this cell line, we have shown that the membrane potential of the cell membrane is sensitive to the small changes in external KCl within the physiological range (2–5 mM), thus functioning as a K+ electrode. When the extracellular K+ was progressively increased (2–5 mM), the membrane depolarization lead to a subsequent increase in [Cl−]i measured by fluorescence quenching of an intracellular chloride sensor. Increase in extracellular [K] resulted in a decrease in the phosphorylation of the WNK4 protein and its downstream targets, SPAK and NCC. This confirms that small changes in serum K can affect WNK4/SPAK/NCC signaling and transcellular Na+ flux through the DCT and provide a possible mechanism by which a K‐rich DASH diet could reduce blood pressure.
Highlights
Hypertension is a major public health issue among industrialized nations, and several clinical and epidemiological studies have shown a clear link between dietary Na+ intake and blood pressure
Hypertension, http://omim.org/entry/145260) and Gitelman (OMIM http://omim.org/entry/263800) have shown that mutations in ion channels and transporters and/or their regulators such as WNK proteins in the nephron perturb the Na+/K+ homeostasis and cause significant changes in blood pressure. The distribution of these proteins along the nephron reflects the key importance of these nephron segments including the loop of Henlé (LoH), the distal convoluted tubule (DCT), and the contiguous segments of the connecting tubule (CNT) and
In the DCT, the WNKs are degraded by the proteasome pathway when they are targeted by a kelch‐like protein 3 (KLHL3) mediated ubiquitylation by Cullin3 (Cul3) (Ohta et al, 2013; Schumacher et al, 2015)
Summary
Hypertension is a major public health issue among industrialized nations, and several clinical and epidemiological studies have shown a clear link between dietary Na+ intake and blood pressure. Hypertension, http://omim.org/entry/145260) and Gitelman (OMIM http://omim.org/entry/263800) have shown that mutations in ion channels and transporters and/or their regulators such as WNK proteins in the nephron perturb the Na+/K+ homeostasis and cause significant changes in blood pressure. The distribution of these proteins along the nephron reflects the key importance of these nephron segments including the loop of Henlé (LoH), the distal convoluted tubule (DCT), and the contiguous segments of the connecting tubule (CNT) and. A fluorescence‐based approach was used to directly show that increasing [K+]o depolarizes the cells and causes subsequent inactivation of the WNK/SPAK/NCC cascade
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