Aldosterone and Mineralocorticoid Receptor Signaling as Determinants of Cardiovascular and Renal Injury: From Hans Selye to the Present

Abstract

<b><i>Background:</i></b> A full understanding of the mechanisms of action of aldosterone and its interaction with the mineralocorticoid receptor (MR) allows a theoretical framework to predict the therapeutic potential of MR antagonists (MRAs) in CKD, and heart failure with reduced ejection fraction. <b><i>Summary:</i></b> The initial focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function. In contrast, many recent studies have demonstrated a wider and expanded role for aldosterone in modulating inflammation, collagen formation, fibrosis, and necrosis. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of CKD. By promoting inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and its associated morbidity and mortality. In accord with this mechanism of action, blockade of the MR is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes who were treated with finerenone (a novel nonsteroidal MRA) manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure, or a sustained decrease of ≥40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). <b><i>Key Messages:</i></b> Based on the success of the FIDELIO-DKD study, future studies should be implemented testing the hypothesis that a wide array of nondiabetic CKD is modulated by overactivation of the MR, and consequently may be amenable to treatment with novel nonsteroidal MRAs. Future studies are encouraged to elucidate the clinical implications of the interplay of nonsteroidal MRAs and the components of the renin-angiotensin cascade. The unique and recently reported interrelationship of fibroblast growth factor (FGF23) and aldosterone may also constitute a propitious subject for future investigation.

Efficacy and Safety of Finerenone in Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

“…Bakris's study (Bakris et al, 2020) showed the that eGFR decreased more slowly with finerenone than with placebo after 4 months; the decrease in eGFR was smaller with finerenone after about 26 months. In addition to a regulatory role in electrolytes and fluid homeostasis in the kidney, MR activation exerts direct effects on the heart and vasculature, including stimulation of inflammation, collagen formation, fibrosis, and necrosis (Lattenist et al, 2017;Epstein, 2021). Finerenone controls inflammation by promoting the expression of M2-anti-inflamatory markers and reducing the population of inflammatory CD11b+, F4/80+, and Ly6C high macrophages (Barrera-Chimal et al, 2018).…”

“…The adrenal steroid hormone binds the mineralocorticoid receptor (MR), promoting sodium retention and potassium loss and thereby controlling the electrolyte status. Considerable evidence supports a pathophysiological role of aldosterone via MR overactivation in CKD and cardiorenal diseases through induction of inflammation and fibrosis that leads to progressive kidney and cardiovascular dysfunction (Bakris et al, 2021;Epstein, 2021). In addition, cardiovascular disease (CVD) is the leading cause of death and morbidity in people with chronic kidney disease (Epstein, 2015).…”

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…The search led to the discovery of non-steroidal MRA; currently, the most advanced compounds are apararenone, esaxerenone and finerenone. They differ from steroidal MRA in their pharmacokinetics, tissue distribution, mode of action, effects on cofactor recruitment and effects on inflammation and fibrosis [30].…”

“…Mineralocorticoids are steroid hormones; the main physiological mineralocorticoid is aldosterone. It is synthesized in the outer layer of the adrenal gland in response to hyponatremia and hyperkalemia, through the activation of the renin-angiotensin system (RAS) [30]. However, it can also be produced locally in peripheral tissues [31].…”

“…It has a higher bioavailability than spironolactone since only fifty percent of it is bound to plasma proteins [60]. Its half-life is 4-6 h and it has no active metabolites [30]. In spite of its short half-life, its anti-mineralocorticoid activity can last up to 12 h, probably because of downstream MR signaling inhibition leading to natriuresis over time [60].…”