Aldosterone Secretion, Genes And Diet

A high potassium diet is the single most important factor to prevent hypertension. There is more extensive evidence for the role of the dietary potassium sodium ratio than for any of the other factors that may be involved in hypertension. There is evidence from epidemiological studies, population studies, basic physiological studies, and animal and tissue studies. Presently many studies are being done at the cellular and molecular levels to determine how processes at these levels cause hypertension.

We previously discussed, in this post, how a fully developed hypertensive heart failure model has shown the importance of a high potassium diet. The model is complete from the level of the heart organ to the level of molecules in the heart cells.

Aldosterone Synthase
Aldosterone Synthase
Aldosterone Secretion, Potassium And Hypertension

The model for aldosterone secretion by the adrenal gland is not as complete as the heart failure model. This is an important model because of the central role of aldosterone and the RAAS (renin-angiotensin-aldosterone system) in the development of hypertension. Potassium and the potassium sodium ratio play a central role here, just as they do in hypertensive heart failure.

By studying at the cellular level abnormal secretion of aldosterone by adrenal gland cells, such as occurs in primary aldosteronism, researchers can more fully understand how hypertension occurs. And they can possibly devise methods for how it can be prevented.

Primary aldosteronism is the main cause of secondary hypertension. Sometimes it runs in families. Sometimes it is caused by a tumor in the adrenal gland. It signifies that too much aldosterone is being produced by the adrenal gland(s) without outside stimulation. This is one of the same mechanisms that cause primary hypertension. And the end result is the same – high blood pressure.

Hypertension Genetics

By studying the cellular abnormalities in primary aldosteronism researchers can also learn a great deal about how primary hypertension occurs. In 2013 a European Journal of Endocrinology published its prize lecture (1) about the genetics of primary aldosteronism. The publication gave a nice summary of what was then known about primary aldosteronism at the cellular and genetic level. The publication reveals a great deal about how potassium can affect adrenal cells. The article also reveals at the cellular level how an increase or decrease in the blood level of potassium causes changes in aldosterone secretion, and thus in blood pressure.

The report discusses the multiple studies done on adrenal cells, many of which the author's group did, especially in primary aldosteronism. The author discusses genetic studies on animals and human genomes. These studies have identified genes that are associated with increased aldosterone. Many of the abnormal genes were found to control the proteins in potassium channels, and the proteins involved in transporting potassium for the sodium potassium ATPase pump.

These abnormal proteins cause these channels and pumps to handle potassium so poorly that there is not enough potassium inside the cell to maintain the electrical charges needed for normal cell function. This is the same problem that occurs when not enough potassium (or too much sodium) is in the diet. The result is excessive secretion of aldosterone and a rise in blood pressure.

The Basics

Before discussing the article, let's review the previously known basics. Many years ago researchers showed that an increase in extracellular potassium leads to an increase in aldosterone secretion into the blood stream. This initiates a series of reactions that lead to an increase in blood pressure. However the increase in blood pressure is just one of many effects previously discovered. An excessive aldosterone blood level, even without an increase in blood pressure, damages the cardiovascular system and the kidney.

Today's Research

Much research today focuses on what happens inside cells. To study aldosterone secretion, molecular pathways inside the cell and the genes that affect the pathways are being studied. Much of the work is being done on mice with experimentally produced changes in their genes. They have what are called knockout genes, which are specific genes that no longer function.

Many of the genes leading to excessive aldosterone secretion are genes that affect the electrical charge of the cell membranes in the cells that secrete aldosterone. The electrical charge is determined by the function of potassium channels, sodium potassium pumps, and intracellular calcium. Calcium controls much of the signaling inside the cell, and is affected by channels and pumps itself.

One of the genes that was studied was the gene that makes the enzyme (pictured above) that makes aldosterone in the adrenal cells. Potassium outside the cell (and angiotensin II) regulates the gene that makes this enzyme. Very minor changes in the extracellular potassium concentration control a signaling cascade. The potassium causes a change in the calcium concentration inside the cell. The calcium change starts a cascade of signaling molecules. The final signaling molecule reaches the DNA in the nucleus to upregulate (or downregulate) the gene so more (or less) enzyme is made.

This cascade happens within minutes of the change in potassium concentration. And it continues to occur for days (even years) when there is chronic stimulation. There are a great many specific types of potassium channels in the cells that make aldosterone. Changes in any of these specific channels affect the electrical charge of membranes in the cell. This in turn affects molecular reactions in the cell. These reactions affect the production and secretion of aldosterone. An increase in aldosterone secretion occurs with these abnormal genes, even when renin (another molecule affecting blood pressure) stays low.

Circadian Rhythm And Hypertension

Interestingly, the researchers also discovered how our circadian rhythm was involved in aldosterone secretion. One of the genes that was knocked out in these mice was a gene that is a core gene for the circadian clock. This circadian clock gene was found to affect aldosterone secretion from the adrenal gland cells. The researchers found that high salt intake increased the secretion of aldosterone in these animals. Furthermore they found that a constant daily salt intake resulted in aldosterone-dependent weekly rhythms of sodium storage (along with water weight) in the body.

Genome Wide Association Studies (GWAS)

This method has been used to identify genes involved in many different diseases. For diseases related to aldosterone, DNA arrays from patients with adrenal tumors and familial adrenal syndromes are used to study a large quantity of genes. Variations in how frequently a gene occurs show an association that can be further investigated as possibly causing a change in aldosterone secretion.

These studies are the type of studies we discussed here. That post discussed a study that identified 130 hypertensive genes. The majority of the genes were associated with potassium, sodium and calcium activity.

Other Genetic Methods

The author's group has used other genetic methods to identify genes that lead to excessive aldosterone secretion. These genes involve some specific potassium channels that allow calcium in the interior of the cell to start the cell signaling process for aldosterone secretion.

Another pair of genes they identified affects proteins carrying potassium to the sodium-potassium-ATPase pump. They found that the pump was slowed, resulting in a change in the electrical charge of cell membranes that led to more aldosterone secretion.

There have been more and more studies on how cells that secrete aldosterone increase their aldosterone secretion, and thus increase blood pressure. The electrical charge of the membranes in the cell is the key factor. This charge is determined by the potassium sodium ratio inside and outside the cell. When the charge cannot be maintained at an appropriate level, aldosterone secretion is affected.

Studies of the genes that cause increased aldosterone secretion are consistently showing how critical the potassium channels are. These channels are critical to maintaining the proper level of potassium inside cellular compartments. The proper level of potassium is critical to maintaining correct electrical charges throughout the cell. When potassium is genetically prevented from maintaining a proper level inside aldosterone secreting cells, hypertension results.

More common than this genetic prevention of potassium balance is dietary prevention of potassium balance. Too little potassium (or too much sodium) in the diet will mean that there will be too little potassium inside the cell. This will lead to improper electrical charges throughout the cell. No matter what causes these improper electrical charges, the result will be the same as occurs with the genetic changes. Aldosterone will be affected. Hypertension and organ damage will result.

Food Tables

To find links to tables of the amounts of potassium and sodium in various foods, click on the List Of Posts tab at the top of the page.
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1. Regulation of aldosterone secretion: from physiology to disease. Beuschlein F. Eur J Endocrinol. 2013 Apr 24;168(6):R85-93. doi: 10.1530/EJE-13-0263. Print 2013 Jun. Only on-line access to full article is from abstract at: http://www.ncbi.nlm.nih.gov/pubmed/23568484