A large body of evidence implicates the renin-angiotensin system in the pathogenesis of cardiovascular disease. However, not everyone understands that the magnitude of the risk reduction achieved in clinical trials with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is only a fraction of the residual risk for cardiovascular events and death. This paper addresses limitations of current therapeutic approaches based on renin-angiotensin system blockade for hypertension and cardiovascular disease by illustrating the complex biochemical physiology and mechanism of classical and alternate angiotensin peptide formation. Emerging evidence of alternate mechanisms that bypass both renin and angiotensin-converting enzyme to produce the angiotensins in tissues and cells is not currently universally recognized. Currently available treatment would benefit from further insights to help fully meet the aims of patient care, and the challenge is to delve more deeply into the renin-angiotensin system cascade, with the aim of enhancing therapeutics for renin-angiotensin system inhibition. This article provides a reappraisal of the renin-angiotensin-aldosterone cascade, highlighting newly elucidated intermediary components and interplay, and their consequent implications and relevance for understanding the long-term contribution of angiotensin II in cardiovascular diseases and their therapy.
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.
Chronic kidney disease (CKD) in type 2 diabetes is a large and growing problem leading to end-stage kidney disease, atherosclerotic cardiovascular disease, and heart failure (HF). Aldosterone is a key risk factor in promoting inflammation and fibrosis, which causes cardiorenal failure. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers does not prevent overactivation of the mineralocorticoid receptor. Therapeutic options and challenges with blocking MR overactivation by aldosterone are reviewed herein. Whereas classic steroidal mineralocorticoid receptor antagonists (MRAs) reduced albuminuria in short-term studies of diabetic and nondiabetic CKD, long-term studies evaluating hard endpoints such as loss of kidney function were not conducted in CKD because of side effects (primarily hyperkalemia). Novel nonsteroidal MRAs reduce proteinuria and markers of HF, with lower risk of hyperkalemia and without renal impairment, in comparison to steroidal MRAs. Furthermore, recent clinical trials have demonstrated the efficacy of the novel, selective, nonsteroidal MRA finerenone to delay progression of kidney and cardiovascular disease, including HF, in patients with CKD and type 2 diabetes. Concomitantly, the safety profile of finerenone is good, with few patients discontinuing treatment because of hyperkalemia, even among study participants with a low estimated glomerular filtration rate (>25 ml/min per 1.73 m2). Novel nonsteroidal attractive addition to the treatment paradigm in the management of patients with CKD and type 2 diabetes, overactivation.
Aldosterone controls salt-water homeostasis by acting on the mineralocorticoid receptor (MR), a ligand-activated transcription factor, in kidney epithelial cells. However, it is now evident that the MR is expressed in multiple cell types and tissues, acting as a key driver of cardiovascular disease. MR antagonists have proven to be highly efficient in patients with heart failure and reduced ejection fraction, and they are a cornerstone of contemporary therapy. In the past decade, a series of experimental studies using models with cell type-specific MRs uncovered the cellular and molecular mechanisms underlying its detrimental effect on left ventricular remodeling. Based on these findings, the potential of MR antagonists has been evaluated in other cardiovascular diseases, including coronary artery disease, arterial hypertension, heart failure with preserved ejection fraction, pulmonary hypertension, atrial fibrillation, and heart valve disease. The present review summarizes the current knowledge on MR activation and antagonism in cardiovascular disease.
The recent successful demonstrations that the nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone provides effective kidney and cardiovascular (CV) protection in patients with chronic kidney disease (CKD) and type 2 diabetes constitutes a platform for considering and implementing an array of future clinical trials in patients with nondiabetic CKD. Activation of the MR, with consequent inflammation and fibrosis, should be operative as a pathogenetic mediator not only in patients with diabetic CKD but also in those with nondiabetic kidney disease. Consequently, it is proposed that MR antagonism therapy will be equally efficacious in patients with nondiabetic CKD. Recently, a major new clinical trial has been initiated testing finerenone in patients with nondiabetic kidney disease (FIND-CKD; NCT05047263). A second clinical development program, FIONA, is dedicated to studies of finerenone in children with glomerular and nonglomerular CKD. Finally, the interrelationship of fibroblast growth factor 23 (FGF23), membrane αKlotho (hereafter called Klotho), and aldosterone may be a propitious subject for future investigation. The interplay and intersection of these seemingly disparate yet intricate relationships may unmask novel, and indeed compelling, opportunities for therapeutic interventions that are capable of interrupting the vicious cycle of excess aldosterone/MR activation and FGF23 secretion with concomitant Klotho insufficiency characteristically present in patients with CKD.
