APA Hypertension

To understand how a high potassium sodium ratio in the diet affects blood pressure, it is important to understand how the dietary potassium sodium ratio affects cells. Human population based studies need basic science confirmation. If there are no physiological studies or cell based studies consistent with the population studies for a concept, the concept is probably invalid. For blood pressure, there are a huge number of basic science studies confirming the population based studies that show the importance of the potassium sodium ratio. This website has featured a few of these basic science studies.

APA tumor cells
The most recent research has been on the effect of the potassium sodium ratio on the function of the structures most involved with cell function – channels, transporters and pumps. Comparing cell function in cells with a normal version of a cell structure to function in cells with an abnormal version of that cell structure improves understanding of how that structure contributes to cell function.

Abnormal cell structures have been found in tumors causing hypertension. A large number of these abnormal cell structures are abnormal potassium channels. They are the most common abnormal cell structure in adrenal gland tumors that secrete aldosterone. Aldosterone producing adenomas (APA) are tumors of the adrenal gland that lead to excessive aldosterone levels in the bloodstream, and to hypertension.

Previous posts discussed genetic alterations that lead to hypertension. However genetic causes of hypertension account for only 5 to 10% of hypertension. The vast majority of hypertension is caused by lifestyle choices. Nonetheless, knowing about the genetic alterations can help us to better understand the cellular mechanisms leading to hypertension.

Recent Review

Researchers authored a recent review (1) of aldosterone producing adenomas. The paper reviews the well-characterized genetic alterations that lead to an aldosterone producing adenoma (APA), which is the leading cause of primary aldosteronism. Primary aldosteronism is the leading cause of secondary hypertension.

Two aspects of these tumors have been studied recently. The best understood aspect of these tumors at this time is how they secrete excessive aldosterone. Not as well understood is how the tumors overgrow to form tumors.

Normal Aldosterone Secretion

The normal path for aldosterone secretion is that an increase in potassium in the bloodstream or an increase in angiotensin II in the bloodstream acts on the zona glomerulosa cells. These cells depolarize when exposed to more potassium or more angiotensin II. The depolarization causes the voltage gated calcium channels in the cell membrane to open. This allows calcium to flood into the cell. If it is angiotensin II that causes the depolarization, there is also an increase in inositol triphosphate (IP3) which leads to a release of even more calcium from the endoplasmic reticulum of the cell.

The increase in calcium in the cytoplasm of the cell leads to a cascade of cellular reactions that cause an increase in the enzyme that catalyzes the last step in the manufacture of aldosterone. The aldosterone produced is then secreted into the blood stream. This leads eventually to hypertension in those on the typical Western diet.

The abnormal secretion of aldosterone is aldosteronism. When the increased aldosterone is not a reaction to something occurring in the body, it is considered primary aldosteronism. Primary aldosteronism is the leading cause of secondary hypertension. It is characterized by hypertension that has an increase in aldosterone and a low level of renin.

Main Causes Of Primary Aldosteronism

The two main causes of primary aldosteronism are an aldosterone producing adenoma (APA), a type of adrenal gland tumor, and adrenal hyperplasia. The APA tumor occurs in the zona glomerulosa cells of the adrenal gland. The mutations that have been found in APA tumors have been found most often in potassium channels, but also in calcium channels and in some of the ATPase pumps (both sodium-potassium ATPase and calcium ATPase).

APA Mutations And Primary Aldosteronism

The most common mutations are in a potassium channel that we discussed here. These mutations lead to less potassium and more sodium inside the cell. The normal polarization of the cell membrane cannot be reached, resulting in a chronic depolarization. This chronic depolarization means that the calcium cascade is continuously more active, and more aldosterone is being produced and secreted.

Similarly, a mutation in the sodium-potassium ATPase pump leads to less potassium being moved into the cell and less sodium being moved out of the cell. The result is the same as with the mutations in the potassium channel – a chronic depolarization with abnormal aldosterone secretion.

Some APA tumors have mutations in calcium channels and in calcium ATPase pumps in the zona glomerulosa cells. These mutations lead to a chronically open state of the calcium channels, causing an increase in intracellular calcium, and an increase in manufacture and secretion of aldosterone. This increased aldosterone secretion occurs even though there is not a chronic depolarization of the cell membrane.

The two main potassium channels that are active in aldosterone producing cells are TASK1 and TASK3. A study that is discussed here examined mice that are deficient in the potassium channels TASK1 and/or TASK3. In TASK3 deficient mice, a low renin salt-sensitive hypertension develops. There are some additional aldosterone abnormalities found in mice deficient in TASK1, and in mice deficient in both TASK1 and TASK3. But mutations in TASK1 and TASK3 have not been found in APA tumors.

However a reduction of TASK2 has been reported in APA tumors. This channel is present at a much lower level than the TASK1 and TASK3 channels. It represents only 1 to 10% of the number of channels of TASK1 and TASK3. So it is difficult to determine the role of TASK2 channels in these tumors, and how much they contribute to excessive aldosterone production.

Tumor Growth

As far as growth of these tumors, the genetic findings are not nearly as clear as the findings concerning aldosterone secretion. There are 2 main pathways that are critical to normal adrenal gland growth and development. These pathways are the sonic hedgehog (SHH) and Wnt/B–catenin pathways. Many abnormalities in cellular function and gland development have been found associated with mutations in the genes of these proteins. But few have been associated with APA tumors.

Wnt is part of a key signaling pathway in normal adrenal gland development and in the formation of adrenal tumors. Overexpression of it in human adrenal cells grown in cell culture has resulted in increased aldosterone production. Increased expression of Wnt has been found in some APA tumors.

Mutations of B-catenin have been found in many human tumors, but in only a few APA tumors. In one particular strain of mice, its activation in the adrenal gland resulted in hyperaldosteronism at 10 months of age.

SHH is felt to be important for the proliferation of cells. However when experiments were done invalidating SHH, the adrenal glands were found to be smaller, but the cells appeared to have a normal pattern in the adrenal gland instead of a pattern like an APA tumor. Abnormal SHH has been found in some APA tumors, but its relation to aldosterone secretion has not been studied.

So knowledge of the pathways involved in the growth of APA tumors is not nearly as advanced as the understanding of normal and abnormal aldosterone secretion. At this point, the genes involved in making the adrenal gland cells grow abnormally do not appear to lead to abnormal aldosterone production as often as abnormal genes involved in the structures controlling membrane polarization.

Membrane Depolarization

The degree of membrane polarization is determined by the balance of potassium and sodium inside and outside the cell. No matter whether the balance is determined by a genetic defect or simply a dietary defect, the result is imbalance and excessive aldosterone production. Too much sodium and too little potassium in the diet leads to too much sodium and too little potassium inside the cell, and too small of a difference in charge across the cell membrane (partial depolarization).

The depolarization in the zona glomerulosa cells leads to more aldosterone secreted. More aldosterone secreted leads to more BK channels in the kidney cells. More BK channels leads to more excretion of potassium (which is already too low because not enough was eaten) and more recycling of sodium into the bloodstream (which is already too much because too much was consumed). The extra sodium gets stored in the extracellular space (the area between the cells). Water gets stored with the sodium.

Other cells in the body are partially depolarized (and probably do not function as well as they should) because of the imbalance of sodium and potassium inside and outside the cell. Because of homeostasis there is eventually a balance, but the cell membrane polarization, cellular function, and sodium and water storage all balance out at a different level than they would be at if the amount of potassium and sodium in the diet were better.

So the abnormal genetics of APAs confirm other basic science studies showing that depolarization of the zona glomerulosa cells on a chronic basis leads to hypertension. Depolarization of zona glomerulosa cells is the initial step for an increase in aldosterone secretion. The increased aldosterone secretion leads to hypertension in those on a Western diet.
1. Molecular and Cellular Mechanisms of Aldosterone Producing Adenoma Development. Boulkroun S, Fernandes-Rosa FL, Zennaro MC. Front Endocrinol (Lausanne). 2015 Jun 11;6:95. doi: 10.3389/fendo.2015.00095. eCollection 2015.