Aldosterone and mineralocorticoid receptor signaling as determinants of cardiovascular and renal injury: an extraordinary paradigm shift

Graphical abstract

The past 90 years have witnessed an extraordinary trajectory of scientific discovery relating to aldosterone and mineralocorticoid receptor (MR) activation, and a profound reappraisal of their physiological and pathophysiological roles. Although most reviews hark back to 1953 and the isolation of aldosterone by Simpson et al.,^1,2 in truth we must revert to an earlier decade for a complete picture. Although many readers will date the birth of the discovery of aldosterone (initially called “electrocortin”) to 1953, when Simpson et al. developed a high-sensitivity bioassay allowing characterization of mineralocorticoid activity, there were earlier inklings that foreshadowed this feat. As early as 1950, Quentin Deming and his mentor, John Luetscher, one of the giants of medicine, reported increased sodium retention in patients with heart diseases compared with healthy subjects.³ The publication of a sensitive radioimmunoassay for plasma aldosterone⁴ and a preparation of dispersed zona glomerulosa cells⁵ in 1970 enabled and catalyzed subsequent physiological research, providing the necessary tools for elucidating both aldosterone biosynthesis and regulation.

The MR was subsequently identified in 1987 by Arriza et al.⁶ However, the cloning, localization, and characterization of the glucocorticoid and MR steroid receptors unmasked a paradox. These were all relatively nonspecific receptors—glucocorticoids bound equally well to the MR as did aldosterone. Yet, the plasma levels of cortisol were significantly higher than aldosterone. This raised an obvious question that challenged all investigators: what was the mechanism that conferred the specificity for the cellular action of steroids? The eminent scientist and cardiovascular physiologist John Funder provided an answer that constituted a seminal discovery in the field. Funder promoted the concept that target-tissue specificity is enzyme mediated, not receptor mediated. In mineralocorticoid target tissues, the receptors are selective for aldosterone in vivo because of the presence of the enzyme 11β-hydroxysteroid dehydrogenase, which converts cortisol and corticosterone, but not aldosterone, to their 11-keto analogs. These analogs cannot bind to the MR, thereby providing the requisite specificity.⁷

Subsequent investigations of the mechanisms of action of aldosterone demonstrated its regulatory role in modulating extracellular volume homeostasis and subserving blood pressure control through its effects on sodium reabsorption and potassium excretion.8, 9, 10, 11 In 1954, Jerome Conn described primary aldosteronism, a condition characterized by hypertension associated with hypokalemia, hypernatremia, hypochloremia, and metabolic alkalosis, attributable to autonomous adrenal production from either adrenal hyperplasia or a cortical adenoma.¹² Primary aldosteronism was the first condition to link the electrolyte, blood pressure, and cardiovascular actions of aldosterone.

Recasting our understanding of primary aldosteronism

Although prior studies on primary aldosteronism have reported wide variation in prevalence estimates,^13,14 the disease has been classically regarded by many clinicians as rare and categorical, although emerging evidence indicates that primary aldosteronism is markedly underdiagnosed, in part due to limitations associated with current screening approaches and guidelines.^13,15 A recent landmark publication by Brown et al. demonstrated that, contrary to longstanding belief, the prevalence of primary aldosteronism is high and largely unrecognized.¹⁵ Furthermore, the study provided compelling evidence that severe hypertension and hypokalemia are not prerequisites for the diagnosis of primary aldosteronism; rather, primary aldosteronism can frequently be detected not only in normokalemic hypertensive persons across a wide spectrum of blood pressure categories, but also among normotensive persons.¹⁵ The observations of Brown et al. serve to redefine primary aldosteronism, from a disease historically identified as an infrequent secondary cause of hypertension, to a common syndrome that plays a pivotal role in the pathogenesis of essential hypertension.¹⁵

The true prevalence of primary aldosteronism depends on how it is defined and what population is being considered. The prevalence is highly dependent on the population that is evaluated, as well as on the arbitrary threshold used to determine an aldosterone-to-renin ratio as positive or negative and which of the variety of confirmatory tests is used. A comprehensive review by Yozamp and Vaidya estimated that the prevalence of primary aldosteronism categorized by hypertensive status was 13% to 14% in normotensive patients and 6% to 36% in patients with hypertension.¹⁶ The key take-home message is that primary aldosteronism is highly prevalent within populations where it is not typically considered, such as those with mild-to-moderate hypertension and prehypertension. Indeed, much of what we currently label as “essential hypertension” is, in fact, renin-independent aldosterone-mediated hypertension.^17,18 Consequently, current concepts of primary aldosteronism must be embraced because they have clinically relevant treatment and outcome implications for a much broader patient population.

How the aldosterone paradigm has changed markedly in the past 30 years: a dramatic paradigm shift

As I have detailed in a recent review, we have witnessed a dramatic change in our prevailing view of aldosterone and the MR over the past 30 years.¹⁹ In 2022, one can unequivocally state that aldosterone is no longer an orphan hormone, but rather a prized focus of basic and clinical research. Although aldosterone’s sodium-retaining effects are clearly relevant in defending volume homeostasis in the setting of hypovolemia, we realize that aldosterone is only one of the physiological ligands for MR, and aldosterone raises blood pressure primarily by actions on the vasculature and central nervous system.¹⁹

Since its isolation by Simpson et al. in the 1950s, all the aldosterone-mediated effects were originally believed to be confined to just a few target organs of epithelial origins. However, in the past decades, several studies have expanded the spectrum of compartments and tissues in which aldosterone appears to exert its activity.²⁰

A better understanding of aldosterone’s true role constitutes a rational framework for examining the therapeutic potential of MR antagonists (MRAs) in chronic kidney disease (CKD), heart failure with reduced ejection fraction, and hypertension. An understanding of the complex interplay between aldosterone and the MR is necessary to appreciate and leverage these physiological and pathophysiological frameworks.^19,21

What is the role of aldosterone in renal physiology?

• •The steroid aldosterone is the main mineralocorticoid hormone; it is synthesized in response to hyperkalemia or sodium and volume depletion as the end point of activation of the renin-angiotensin system (RAS).¹⁹
• •Aldosterone acts through the MR, which is expressed in many tissues, including the kidney, colon, heart, central nervous system, brown adipose tissue, and sweat glands.^8,19,21,22
• •Aldosterone plays a major role in both the control of blood pressure and maintaining extracellular volume homeostasis by stimulating renal sodium reabsorption and potassium excretion.^19,21

Figure 1 summarizes how our understanding of the role of aldosterone has changed over the past 30 years. In 1990, an understanding of the interaction between aldosterone and the MR was as follows:

• •Angiotensin (Ang) was the major determinant of aldosterone secretion.¹⁹
• •Aldosterone was the sole physiological ligand for MR.¹⁹
• •Aldosterone elevated blood pressure primarily by its sodium-retaining effects, leading to volume expansion.¹⁹
• •MRAs acted by blocking the binding of aldosterone to MR.¹⁹
• •Aldosterone acted genomically and nongenomically.¹⁹

Figure 1.

A summary of the expansive trajectory of the mineralocorticoid receptor (MR) from its initially circumscribed role in supporting volume homeostasis and blood pressure regulation to the present. The MR is currently recognized to be activated by several ligands (e.g., aldosterone and cortisol) and by nonligand activation. The MR is expressed in many tissues, including the kidney, colon, heart, and central nervous system. Not depicted in the figure is the more recent recognition of the intersection and interplay of MR activation and the fibroblast growth factor-23/Klotho cascade, and its role in promoting cardiorenal injury (which is detailed in the article by Epstein²³ in this supplement). ACE, angiotensin-converting enzyme; Rac1, Ras-related C3 botulinum toxin substrate 1.

A paradigm shift in the understanding of the role of aldosterone over the past 30 years (Figure 1) means it is now accepted that:

• •Ang does not constitute the major driver of aldosterone secretion.¹⁹
• •The MR is activated by several ligands (aldosterone and cortisol) and nonligand activation (Ras-related C3 botulinum toxin substrate 1, elevated glucose, and high salt levels).^21,22
• •Aldosterone raises blood pressure primarily by actions on the vasculature and central nervous system, although aldosterone’s sodium-retaining effects are relevant in defending volume homeostasis in the setting of hypovolemia.¹⁹
• •Leptin is a newly described regulator of aldosterone synthesis that acts directly on the adrenal glomerulosa cells to increase aldosterone synthase (CYP11B2) expression and enhance aldosterone production via calcium-dependent mechanisms.²⁴

In 2022, it has been clearly established that aldosterone and MR activation promote a wide array of renal and cardiovascular injury, including the progression of CKD and cardiovascular disease as well as heart failure with reduced ejection fraction, arterial stiffness, and the metabolic syndrome.^8,19,21 The contributors to this supplement were asked to critically review the available literature dealing with the wide array of facets of the normal physiology and pathophysiology of CKD, MR activation/antagonism, enzyme cascades, and wider system pathologies.

The first article by Kovesdy²⁵ reviews the epidemiology of CKD. The author reviews the laboratory findings and inclusion of a so-called “chronicity criterion” used to determine the presence of CKD. Kovesdy also highlights the increased associated mortality observed over the past 2 decades, prompting the need for increased therapeutic efforts aimed at retarding the development of CKD and slowing its progression.

The next article by Nakamura et al.²⁶ highlights the central role of MR signaling in CKD progression, and the contribution of the MR to inflammation and fibrosis in disease pathogenesis. In addition to the expression of the MR in renal epithelial cells, it is also found in nonepithelial cells. Data are presented from preclinical models and in vitro studies that succeed in elucidating the role of the MR in nonepithelial cells. Building on this platform, the authors discuss several potential targets that offer opportunities for the targeting of MR signaling in nonepithelial cells.

MR expression and activation beyond the renal epithelium are examined further in the article by Bauersachs and Lother.²⁷ The authors explore MR activation as a key driver of cardiovascular disease and review evidence from several experimental studies demonstrating that MRs in many cell types, including cardiac myocytes, endothelial cells, smooth muscle cells, myeloid cells, T cells, and osteoblasts, have a direct impact on heart failure and other cardiovascular diseases. Depending on the type of disease or stimulus, different cell types have MRs with distinct functions that contribute to the cumulative effects of inflammation and fibrosis after activation. The available insights discussed in this review will provide the basis for further development and the evaluation of classic and novel nonsteroidal MRAs for additional cardiovascular indications.

Building on the evidence from the previous articles, Rossing²⁸ reviews the use of MRAs for the management of patients with diabetes mellitus and related CKD and cardiovascular complications. The author surveys the current options and challenges that are encountered with blocking MR overactivation, including the risk of hyperkalemia. He also provides an overview of the promising novel nonsteroidal MRAs, a potential solution to overcoming these challenges when administered in concert with RAS inhibition.

The current therapeutic approaches utilizing RAS blockade for managing cardiovascular disease and hypertension are critically reviewed in the next article by Ferrario et al.,²⁹ who delve deeper into the RAS cascade and examine evidence of renin-independent noncanonical pathways that produce Ang II. These pathways are largely unaffected by agents inhibiting RAS activity. As such, Ferrario et al. explore alternative future efforts (e.g., focusing on blocking the synthesis or action of intracellular Ang II, and inhibiting chymase, the primary Ang II–forming enzyme in the heart). Ferrario et al. also review basic research studies that reveal the broad actions of Ang-(1-12) as an Ang II–forming substrate. The demonstration of augmented circulating Ang-(1-12) in hypertensive patients suggests a participatory role of this substrate as a potential biomarker for hypertension, with a discriminative value greater than that of circulating angiotensinogen and even Ang II.

In a subsequent article by Hollenberg and Epstein,³⁰ proteolytic enzymes and enzyme cascades are further examined in the contemporary context of coronavirus disease 2019 (COVID-19). The underlying mechanisms that drive the innate immune response, such as activation of microenvironment proteolytic enzymes either individually or amplified by several cascades, including the coagulation and complement systems, are reviewed. The authors emphasize the role of the innate immune response system involving both proteinases and innate immune cell responders, paying special attention to proteolytic enzymes that act in the immediate extracellular microenvironment of tissues, thereby driving inflammatory signaling. We anticipate that continued interrogation of the therapeutic targets delineated in this overview will succeed in helping define new treatment paradigms, which may mitigate acute and chronic infectious diseases that can begin in the lungs, with an emphasis on COVID-19. Furthermore, such interrogations may also provide a template for further understanding the determinants of fibrosis that impair an array of target organs, including the kidney and the cardiovascular system as well as other tissues.

The penultimate article by Luther and Fogo³¹ explores the role of MR activation in kidney inflammation and fibrosis. The initial part of the article reviews the pathophysiologic mechanisms promoting kidney fibrosis in CKD, and the antifibrotic and anti-inflammatory roles of MR antagonism. In subsequent sections, the authors examine how aldosterone promotes fibrosis and inflammation and discuss the roles of plasminogen activator inhibitor-1 and transforming growth factor-β as modulators of aldosterone-induced fibrosis. The authors then discuss the MR activation–related stimulation of glomerular and epithelial inflammatory pathways and the promotion of macrophage polarization and kidney inflammation.

In the final contribution, entitled “Considerations for the future: current and future treatment paradigms with mineralocorticoid receptor antagonists—unmet needs and underserved patient cohorts,”²³ I will close the circle by updating established paradigms in physiology, pathophysiology, and clinical science and consider both current established concepts in physiology, pathophysiology, and clinical science and treatment considerations for the future. In addition to demonstrating that novel nonsteroidal MRAs, such as finerenone, constitute an effective treatment for kidney and cardiovascular protection in patients with type 2 diabetes, I propose that the FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) study should constitute a platform for implementing an array of future clinical trials to address unmet needs and underserved patient cohorts. Examples of studies of great interest include examination of the heretofore unappreciated intersection and interplay of MR activation and alterations of the fibroblast growth factor-23/Klotho axis. Implicit in my formulation is the hypothesis that, when acting in tandem, these parallel endocrine cascades accelerate and exacerbate the trajectory to renal and cardiovascular injury.³²

Another clinical disorder that invites further investigation is sickle cell disease–associated nephropathy. As I will discuss in this article, this cohort of interest constitutes a major global burden of disease and is underserved. Adults with sickle cell disease are at an increased risk of CKD and progression to end-stage kidney disease as they age, and the available modalities for renal replacement treatment in patients with CKD caused by sickle cell disease are replete with challenges. Preclinical studies have suggested the possibility that MR activation may participate in promoting the progression of sickle cell disease–associated nephropathy. Overall, the FIDELIO-DKD and FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease (FIGARO-DKD) studies support not only the clinical benefit of finerenone in patients with CKD and type 2 diabetes, but also the huge clinical opportunity that now exists to leverage their results into exploring novel therapeutic approaches in many future investigations in this setting.

Disclosure

This article is published as part of a supplement sponsored by Bayer AG.

ME reports personal fees from Alnylam Pharmaceuticals, Bayer, and Vifor Pharma, outside the submitted article. ME received no personal funding for this article.