Molecular Insights into How a Western Diet May Promote Hypertension

New research on the sodium-chloride cotransporter (NCC) and its mechanisms provides a clearer understanding of how a typical Western diet—high in sodium and low in potassium—could promote hypertension. In a study presented at Kidney Week 2013, Andrew Terker, an MD/PhD student at the Oregon Health & Science University, and coworkers found this diet profile may play a role in the development of hypertension in an NCC-dependent manner. Although the results need to be confirmed in human studies, this insight could further inform research about dietary sodium’s role in hypertension, an area of continuing controversy.

“The mechanics of NCC are understood, but modifications of activity are still in progress, such as was shown in this nice study,” said Matthew Weir, MD, of the University of Maryland School of Medicine, who was not affiliated with the study.

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Terker and colleagues used three different animal models to determine NCC’s effects on the mechanics of blood pressure homeostasis in the kidney. The first modeled primary aldosteronism and researchers observed an increase in total and phosphorylated NCC. Potassium wasting was observed in NCC knockout mice, but not in wild-type controls. A pseudohypoaldosteronism type I simulation found that in addition to the expected hyperkalemia, total and phosphorylated NCC levels dropped dramatically.

In the final series of experiments, high-salt diets were administered, in combination with either a normal amount of potassium or no potassium added, to both wild-type and NCC knockout mice. Terker found the Western diet (high in sodium and low in potassium) caused a large increase in total and phosphorylated NCC, as well as increases in the enzyme WNK4 (an important molecular switch expressed in the distal nephron) and SPAK. Most important, the diet decreased urinary sodium in wild-type mice but not in NCC knockout mice.

The results are biologically plausible and concordant with previous clinical work showing that higher sodium and lower potassium in the diet results in higher blood pressure, said Weir. “Clinically, higher potassium in the diet helps lower blood pressure on a high sodium diet,” he added.

“Our work indicates that NCC primarily functions to regulate potassium, perhaps at the cost of blood pressure increases,” said Terker. “For patients, this means that increasing dietary potassium may prevent sodium retention by inhibiting NCC, even on a high salt diet.”

Terker said the next steps in their research are to determine the molecular mechanism mediating the effect of potassium on NCC function and to test if this effect is observed in humans.

Reference

1. 

Terker A, et al. A Western Diet Activates NCC to Promote Sodium Retention. J Am Soc Nephrol 2013; 24 (Suppl):30A (Abstract)