Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine

Rajiv Agarwal; Peter Kolkhof; George Bakris; Johann Bauersachs; Hermann Haller; Takashi Wada; Faiez Zannad


Eur Heart J. 2021;42(2):152-161. 

In This Article

Molecular Mechanisms of Mineralocorticoid Receptor Antagonism and Cardiorenal Protection: Lessons From Animal Models

Following cloning of the MR gene in 1987,[38] a series of recombinant MR animal models provided molecular insights into the mechanism of action of this receptor (Supplementary Material Online, Table S1). Collectively, these studies demonstrate that, although the MR is essential for normal kidney and cardiac function,[39] overactivation leads to increased reactive oxygen species, inflammation and fibrosis, and ultimately, kidney and CV disease.

In utero complete MR knock-out (MRKO) was lethal within 10 days of birth, eliciting a phenotype of severe pseudohypoaldosteronism in mice, underscoring the critical importance of the MR in salt, water, and BP maintenance during development.[40] As expected, an elevated concentration of renin and aldosterone, and decreased epithelial sodium channel (ENaC)-mediated Na+ transport was observed in the colon and kidneys.[40] The latter occurred without a reduction in the mRNA abundance of ENaC, suggesting post-transcriptional effects.[40] In contrast, MRKO limited to the principal cells of renal tubules permits survival to adulthood; however, abundant dietary sodium is required to compensate for reduced ENaC trafficking.[41–43] In contrast, MR overexpression results in abnormalities such as renal enlargement and cardiomyopathy and can be lethal in utero or the early postnatal period.[44,45]

Cardiomyocyte MRKO has been evaluated in various forms of cardiac disease. In an MI mouse model, compared with wild-type controls, MRKO resulted in a number of salutary effects including increased infarct healing, increased myocardial capillary density, decreased pulmonary oedema, improved cardiac remodelling, and reduced contractile dysfunction.[46] Cardiomyocyte MRKO prevented MI-associated up-regulation of Nox2 and superoxide production; reduced extracellular matrix deposition; and increased stress-induced activation and subsequent suppression of nuclear factor-κB and decreased apoptosis.[46] Reduced inflammation and fibrosis was also demonstrated with cardiomyocyte MRKO in a DOCA–salt-induced mouse model of cardiac fibrosis; these effects were BP independent.[47] The cardiomyocyte MRKO model elegantly demonstrates the dissociation between haemodynamic and pro-inflammatory/pro-fibrotic effects of MR activation.

Myeloid MRKO has perhaps contributed the most intriguing results to understanding the molecular physiology and pathophysiology of the MR, suggesting a novel immune mediation of inflammatory and fibrotic processes leading to organ dysfunction. Surprisingly, in a mouse model of glomerulonephritis, podocyte MRKO provided no kidney protection vs. wild-type controls; cystatin C (a marker of kidney function) and histology were similar between groups.[48] Contrastingly, myeloid MRKO was renoprotective, with reduced proteinuria vs. wild-type controls.[48] Importantly, whereas eplerenone-treated wild-type mice also had reduced proteinuria, unlike myeloid MRKO, eplerenone use was associated with impairment in kaliuresis.[48] This is particularly relevant in providing direct evidence of kidney protection by tissue/cell type-selective MR antagonism, without hyperkalaemia.[48] Myeloid MRKO has also been shown to be protective against cardiac hypertrophy, fibrosis, and vascular damage. This is intriguing because myeloid MRKO induced a BP increase relative to wild-type mice, not a reduction.[49] Furthermore, an ischaemic reperfusion model in myeloid MRKO demonstrated a 65% reduction in infarct volume vs. controls.[50] An important role for the MR in inflammation and fibrosis in cardiac disease was identified in this model—compared to wild-type controls, myeloid MRKO mice exhibit a transcription profile of alternative activation in macrophages,[49] decreased recruitment of macrophages, suppression of M1 macrophages, and partial restoration of M2 macrophages.[41,50] Further research showed that activation of the c-Jun NH2-terminal kinase pathway in macrophages after tissue injury is implicated in downstream inflammation and fibrosis.[51]

The glucocorticoid-inactivating enzyme 11 beta-hydroxysteroid dehydrogenase 2 (11βHSD2) inactivates cortisol in the kidneys, colon, and sweat glands, and its blockade results in activation of the MR by cortisol due to its equal affinity but higher abundance relative to aldosterone.[52] Differential MR effects between the heart and kidneys may be mediated by differential 11βHSD2 tissue expression.[52,53] For example, 11βHSD2 is present in the distal nephron epithelium, where aldosterone activates the MR to stimulate sodium and potassium transport[53] but is absent in cardiomyocytes, podocytes, and macrophages,[53] suggesting cortisol as the major active MR ligand in these cells. Increased plasma aldosterone has been reported with long-term ACEi/ARB use in patients with congestive HF, CKD, or hypertension, because of incomplete suppression of serum aldosterone levels (aldosterone breakthrough), which may contribute to MR overactivation.[54]