Advancing cardiorenal health:
Scientific insights into aldosterone dysregulation

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The need for innovation in hypertension – a silent killer causing devastating harm to the body – has never been greater. Globally, in 2019, ~1.3 billion adults had hypertension.¹ Despite the availability of multiple treatments, around 70% of adults with hypertension in the US between 2017 and 2020 remained above blood pressure targets—even when taking medication.²

At AstraZeneca, we are focused on addressing hard-to-control hypertension, which includes both the uncontrolled hypertension (blood pressure consistently above target despite two antihypertensives from different classes) and resistant hypertension (blood pressure consistently above target despite three or more antihypertensive medications or when control is achieved but requiring ≥ 4 antihypertensive medications) patient populations.^1,3

For patients with hard-to-control hypertension, an overlooked driver of elevated blood pressure might be dysregulated aldosterone.

What is aldosterone?

Aldosterone is a mineralocorticoid steroid hormone produced by the adrenal glands that plays a crucial role in regulating fluid and electrolyte balance in the body, making it integral to homeostasis. Its primary function is to help regulate blood pressure by signaling certain organs to increase the amount of sodium they send into the bloodstream, or the amount of potassium expelled in urine. Overall health is impacted when the body produces too little or too much aldosterone. Aldosterone production is part of renin-angiotensin-aldosterone system (RAAS).^4-8 Dysregulation of this critical physiological feedback loop, particularly the upregulation of aldosterone, can contribute to hypertension, heart failure, and kidney disease.⁹

The RAAS pathway and aldosterone production

The kidneys release renin in response to various stimuli, including low blood pressure (as detected by baroreceptors), decreased blood volume, and sympathetic nervous system activation, otherwise known as “fight or flight.”^8,10 Functioning as an enzyme, renin catalyses the production of angiotensin I, which is then converted into angiotensin II, a vasoconstrictor that reduces the diameter of blood vessels, leading to increased blood pressure.⁸

Angiotensin II also stimulates the adrenal glands to release aldosterone.^5,6,8,14,15 Notably, the enzyme that catalyses the production of aldosterone, aldosterone synthase, shares a similar shape with 11β-hydroxylase (a 93% sequence similarity), which is responsible for the production of cortisol.^15-17 This structural similarity has made it difficult to develop a cortisol sparing therapy, i.e., one that selectively suppresses aldosterone, but not cortisol production.

Aldosterone promotes potassium excretion in urine. Along with antidiuretic hormone (ADH), it enhances sodium and water reabsorption. This interplay regulates blood volume and pressure, completing the RAAS feedback loop.^5,8 Essentially, the kidneys sense the increased sodium concentration in the bloodstream and signal to “ease off the gas” with renin production. Other hormones and corticosteroids that separate from the RAAS pathway, including oestrogen and thyroid hormones, can also trigger aldosterone synthesis.^5,8 Any dysregulation in the RAAS pathway or these hormonal processes could lead to inappropriate aldosterone production.⁵

Inappropriately elevated aldosterone

Aldosterone helps regulate blood pressure, acting as an effector for fluid homeostasis, and indirectly maintains blood pH balance by regulating sodium and potassium.^5-8 Elevated aldosterone levels can be beneficial when salt intake is low or during excessive sweating.^18,19

There are a number of conditions that can lead to inappropriately elevated levels of aldosterone:

• Primary aldosteronism, also known as Conn’s syndrome, is when the adrenal glands produce too much aldosterone. Primary aldosteronism can be caused by adrenal adenomas, adrenal hyperplasia, or familial hyperaldosteronism
  type 1.²⁰
• Secondary aldosteronism, can occur if blood flow to the kidneys is reduced, either due to obstructive renal artery disease or conditions such as heart failure, which will then inappropriately trigger the RAAS pathway.²⁰

Patients with excess aldosterone have a higher risk of adverse cardiorenal outcomes than patients without elevated aldosterone (or patients with elevated aldosterone that is appropriate for their blood sodium concentration).^9,21,22 Studies indicate that there is a high prevalence of aldosteronism among patients with hypertension, particularly in those who have more severe or resistant hypertension.²³

Aldosterone dysregulation occurs as a gradual, continuous process rather than an on/off switch from normal function to dysregulation.²⁴ When inappropriately regulated, the normal feedback loop breaks down so that even when renin levels are low in the presence of triggers such as increased sodium concentration, aldosterone remains high, leading to hypertension and adverse cardiorenal outcomes.^6,7

The cause of this feedback loop breakdown is unknown. However, risk factors may include excessive salt consumption, diabetes, sleep apnea, adrenal adenomas, the presence of aldosterone-producing micronodules, and obesity—all conditions in which blood pressure regulation is disrupted.^6,21,24,25 For example, adipose tissues release leptin, which bypasses the RAAS pathway to stimulate aldosterone secretion.²⁴

Additional roles of aldosterone in disease pathophysiology

In excess, aldosterone can also promote fibrosis by stimulating collagen production, causing scar tissue formation in the heart and blood vessels, and impairing function.^7,26,27 Moreover, aldosterone can induce inflammation and oxidative stress, further contributing to damage in cardiovascular tissues.^7,27,28

Altogether, this inflammatory ecosystem further drives organ damage beyond hypertension alone, with the aldosterone-induced increased blood pressure leading to increased cardiorenal risk and the subsequent cardiorenal dysfunction resulting in end-organ damage independent of hypertension.^6,7,29

Innovation is needed focusing on addressing aldosterone dysregulation.  

The necessity for innovation in hypertension treatment has reached a critical point. Over the past two decades, breakthrough developments for hypertension have been limited, even as the prevalence of hard-to-control hypertension continues to rise.

To learn more about AstraZeneca's cardiovascular research, visit https://www.astrazeneca.com/what-science-can-do/topics/clinical-innovation/leading-cardiovascular-renal-metabolism-innovation.html.

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