Salt Sensitivity And Epigenetics

High potassium foods are foods that are high in potassium and low in sodium, giving a high ratio of potassium to sodium. They are important for the prevention of hypertension. Hypertension is becoming more and more common worldwide, and is the greatest risk factor for stroke, heart attack, and congestive heart failure, as well as for overall death. The possible causes of hypertension are an area of extensive work being reported in the medical literature. Starting approximately 60 years ago sodium became the main area of interest in the study of hypertension. The article (1) to be discussed today goes through a brief history of how salt sensitivity in hypertension came to be studied. It then goes into the modern knowledge of salt sensitivity, emphasizing its molecular mechanisms and epigenetics, and does some speculation on the future.

History

Salt sensitivity epigenetics
Epigenetic Factors
In the 1960s Dahl bred rats that within 3 generations developed hypertension with increased salt intake. This allowed him to study various aspects of how salt influenced blood pressure.

At approximately the same time, Dr. Guyton showed that dietary sodium and the ability of the kidney to get rid of sodium controlled long-term blood pressure. He used an engineering model to show these relationships mathematically. Since his work, this model has been well tested in animals and in patients receiving kidney transplants.

Dr. Guyton showed that those who are sensitive to salt differed from those who were resistant to salt. This is something he labeled the renal function curve. He showed that those who are resistant to salt can excrete more sodium through the kidneys as blood pressure rose. Those who were sensitive to salt (sodium) had a larger rise in their blood pressure for the same amount of sodium excreted.

Dahl's studies showed that there is a genetic role in the sensitivity of blood pressure to salt. Since that time, there have been multiple animal models developed to study the genetics of salt sensitivity. These animals all have genetic makeups that differ from one group of animals to another. These models have shown a great deal about the genetics of hypertension, and about the interaction of genetics with environmental factors, as well as about the interaction of genes with other genes in hypertension.

GWAS

Genetic Wide Association Studies (GWAS) have been discussed previously here and here. They have shown some important single gene changes associated with hypertension. But these gene changes only represent a small percentage of the people who have hypertension. GWA Studies have discovered less than 1% of the estimated genes involved in hypertension. This is because the most common genetic changes associated with hypertension are polygenic (more than one gene) changes. In addition to there being multiple genes influencing the sensitivity of blood pressure to sodium, researchers have found that there are interactions between these genes with each other, and between these genes and the environment.

Salt Sensitivity Epigenetics

For a cell, the environment is the fluid that the cell sits in and the cells that are adjacent to it. This fluid contains sodium and potassium. A major factor in a cell's environment is the concentration of sodium and potassium in this fluid. This factor influences the cell membrane potential. Changes in the cell membrane potential set off multiple cascades of chemical reactions within the cell. Some of these reactions will affect the genes in the cell through epigenetic factors.

For scientists studying epigenetic factors, the exact definition of epigenetics is still evolving. There is debate about whether the epigenetic changes can be inherited. But in this article the authors only consider whether the gene confers “susceptibility” to blood pressure elevation from an epigenetic factor. The authors also use the generally accepted part of the definition of epigenetic factors that they are factors that suppress or activate genes without changing the DNA sequence of the actual gene itself.

These factors are how the environment interacts with the gene, especially how the environment immediately surrounding the gene interacts with it. The epigenetic factors may affect genes by turning them on or off. They affect how the cells read the genes. Sometimes they affect the genes by speeding up or slowing down their expression. Or they may involve other genes that interact with each other. Two gene-environment interactions often cited are methylation of DNA and modification of histones. Histones are proteins that DNA wraps around. If the shape of the histones changes, the genes available for reading will change. This can change how a gene is expressed without changing the gene itself. When this occurs in kidney cells or adrenal cells, it can have an effect on blood pressure.

The authors then go into many potential gene locations and possible influences on these genes that potentially affect sodium sensitivity. Some readers may not be interested in the detailed science in this portion of the publication. The authors discuss several methods of looking at specific suspected genetic determinants of blood pressure. This portion of the article would be of interest to doctors and other researchers who can devise experiments about salt sensitivity based upon the authors' speculations. Nonetheless, this part of the publication shows the importance that dietary sodium has on the level of blood pressure, and on the sequelae of hypertension.

Based on their own work, the authors also present some exciting ways to possibly prevent some of the sequelae of hypertension, such as scarring of the heart or scarring of the kidney. The cellular mechanism of the heart scarring was discussed in this post. The authors discuss their experiments that showed prevention and even some reversal of hypertensive heart scarring. They did this by immunizing animals against a particular molecule that is produced by the heart when there is excessive sodium in the diet. Some experiments they discuss also indicate that this immunization may protect against the scarring in the kidney that occurs from excessive sodium in the diet.

Sodium Is Half The Equation

But excessive sodium in the diet is only one half of the equation. Potassium is the other half. It is the interaction of these two ions that is crucial to blood pressure.

Their interaction is determined by their ratio. When sodium is affected, there is an effect on potassium. If a potassium ion leaves from inside the cell, a sodium ion must enter to take its place. If there is too much sodium outside the cell from too much dietary sodium, some sodium will push into the cell. For every extra sodium inside the cell, a potassium is kicked out.

Either way, excessive sodium and/or inadequate potassium reduces the cell membrane potential and leads to many cellular processes that would not occur with a normal cell membrane potential. On this website multiple posts have discussed this interaction, and multiple posts in the future will also discuss this interaction. All of this interaction is controlled by the potassium and sodium content of the food that you eat. If the foods are high in potassium and low in sodium, the ratio will be optimal.
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1. Molecular mechanisms of experimental salt-sensitive hypertension. Joe B, Shapiro JI. J Am Heart Assoc. 2012 Jun;1(3):e002121. doi: 10.1161/JAHA.112.002121. Epub 2012 Jun 22.