Effects Of Mineralocorticoid Receptor Activation Research Articles

Mineralocorticoid receptor antagonists in diabetic kidney disease - mechanistic and therapeutic effects.

Chronic kidney disease (CKD) is the leading complication in type 2 diabetes (T2D) and current therapies that limit CKD progression and the development of cardiovascular disease (CVD) include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Despite the introduction of these therapeutics, an important residual risk of CKD progression and cardiovascular death remains in patients with T2D. Mineralocorticoid receptor antagonists (MRAs) are a promising therapeutic option in diabetic kidney disease (DKD) owing to the reported effects of mineralocorticoid receptor activation in inflammatory cells, podocytes, fibroblasts, mesangial cells and vascular cells. In preclinical studies, MRAs consistently reduce albuminuria, CKD progression, and activation of fibrotic and inflammatory pathways. DKD clinical studies have similarly demonstrated that steroidal MRAs lead to albuminuria reduction compared with placebo, although hyperkalaemia is a major secondary effect. Non-steroidal MRAs carry a lower risk of hyperkalaemia than steroidal MRAs, and the large FIDELIO-DKD clinical trial showed that the non-steroidal MRA finerenone also slowed CKD progression and reduced the risk of adverse cardiovascular outcomes compared with placebo in patients with T2D. Encouragingly, other non-steroidal MRAs have anti-albuminuric properties in DKD. Whether or not combining MRAs with other renoprotective drugs such as SGLT2 inhibitors might provide additive protective effects warrants further investigation.

Histone demethylase LSD1 deficiency and biological sex: impact on blood pressure and aldosterone production.

Human risk allele carriers of lysine-specific demethylase 1 (LSD1) and LSD1-deficient mice have salt-sensitive hypertension for unclear reasons. We hypothesized that LSD1 deficiency causes dysregulation of aldosterone's response to salt intake resulting in increased cardiovascular risk factors (blood pressure and microalbumin). Furthermore, we determined the effect of biological sex on these potential abnormalities. To test our hypotheses, LSD1 male and female heterozygote-knockout (LSD1+/-) and WT mice were assigned to two age groups: 18 weeks and 36 weeks. Plasma aldosterone levels and aldosterone production from zona glomerulosa cells studied ex vivo were greater in both male and female LSD1+/- mice consuming a liberal salt diet as compared to WT mice consuming the same diet. However, salt-sensitive blood pressure elevation and increased microalbuminuria were only observed in male LSD1+/- mice. These data suggest that LSD1 interacts with aldosterone's secretory response to salt intake. Lack of LSD1 causes inappropriate aldosterone production on a liberal salt diet; males appear to be more sensitive to this aldosterone increase as males, but not females, develop salt sensitivity of blood pressure and increased microalbuminuria. The mechanism responsible for the cardiovascular protective effect in females is uncertain but may be related to estrogen modulating the effect of mineralocorticoid receptor activation.

0268 : Implication of the Neutrophil Gelatinase-Associated Lipocalin (NGAL) from immune cells in aldosterone induced cardiovascular remodeling

Background Inadequate activation of the Mineralocorticoid Receptor (MR) promotes hypertension, inflammation and fibrosis. Neutrophil Gelatinase- Associated Lipocalin (NGAL), a pro-inflammatory/fibrotic glycoprotein, is a direct target of the MR in cardiovascular cells, and is increased in immune cells during inflammation. Recently, we demonstrated that NGAL is crucial for the hypertensive and pro-fibrotic effects of the nephrectomy-aldosteronesalt (NAS) challenge in mice. However, the specific cell types that modulate NGAL production during aldosterone-dependent hypertension are still unknown. The aim of this study was to characterize NGAL expression in mouse immune cells, and to study the effect of MR activation on NGAL and pro-inflammatory cytokines expression in dendritic cells (DCs). Methods Male C57Bl6 mice were submitted to 28 days of NAS challenge (200μg/kg/d). CD4 + , CD8 + T cells, B cells, DCs and Macrophages (Mo) were sorted from spleen. DCs and Mo were cultured from WT and NGAL-KO mice and treated with aldosterone (100nM) for 24h. NGAL and cytokines mRNAs abundance was measured by RT-qPCR. Results NAS treatment induced a selective increase in the recruitment of activated-CD8 + cells, B cells and granulocytes in lymph nodes. NGAL abundance was higher in PBMC, DCs and Mo, and further increased in NAS mice ( In vitro MR activation by aldosterone in DCs induced an upregulation of NGAL and cytokines involved in the adaptive immune response (TGF-β1, IL-23). Interestingly, the absence of NGAL in DCs prevented this increase. Conclusion MR activation and subsequent NGAL induction in DCs could play a pivotal role in the inflammation observed during aldosterone-dependent hypertension. The author hereby declares no conflict of interest

Abstract P071: Mineralocorticoid Receptor Overexpression in Adipose Tissue Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase PTGDS and lipocalin-2 NGAL

Objectives: Metabolic Syndrome (MetS) is a cluster of metabolic risk factors associated with a higher risk for cardiovascular events. Adipose tissue (AT) plays a central role in the obesity-related metabolic abnormalities and it’s known that Mineralocorticoid Receptor (MR) activation affects adipocyte differentiation and function. The purposes of this study were to evaluate the molecular and metabolic consequences of adipocyte-targeted increase in MR expression in mice. Results: In our study we showed that MR expression is increased in visceral adipose tissue (VAT) in a preclinical mouse model of MetS. Thus, we generated a double transgenic mouse model with a conditional and inducible overexpression of MR in AT (Adipo-MORE), demonstrating that increased expression of MR in AT contributes to MetS development with multiple metabolic abnormalities, including visceral obesity (VAT mass, control-MR 5.0±0.6 adipo-MORE 10.4±1.8, p<0.05), insulin resistance (HOMA index, control-MR 8.9±0.8 adipo-MORE 14.5±2.2, p<0.05) as well as dyslipidemia (total cholesterol, mg/dL control-MR 86.0±6.0 adipo-MR 109±6, p<0.05). We also identified prostaglandin D2 synthase (PTGDS) as a novel mediator of adipogenic effects of MR activation in adipocytes. Since adipokines play pivotal roles in the regulation of insulin sensitivity in obesity, we also focused on the role of lipocalin-2 NGAL, recently identified in our laboratory as a target of aldosterone action in cardiovascular system, as new adipocyte MR target. It’s known that NGALKO mice fed a high fat diet are protected from obesity-induced cardiovascular dysfunctions. In our model we observed an increase of NGAL mRNA levels (3 fold increase, p<0.05) in VAT. Moreover, NGAL was induced (2-8 fold increase, p<0.05) in primary cultures of adipocytes differentiated ex vivo from adipo-MORE mice in presence of aldosterone stimulation compared to controls. Conclusions: We demonstrated that PTGDS is a novel direct MR target in rodent adipocytes mediating adipogenic effects of MR activation. We also found that NGAL is induced in presence of MR overexpression in adipocytes in vivo and ex vivo. In consideration of our results, other analyses are necessary to better understand the role of NGAL as adipocyte MR target.

Endothelial Cell Mineralocorticoid Receptors

See related article, pp 1033–1040 Clinically, mineralocorticoid receptor (MR) antagonists are widely prescribed for the treatment of hypertension and heart failure because of their diuretic action in aldosterone-sensitive distal nephron. Clinical trials of MR antagonism in patients with various degrees of heart failure severity have also demonstrated a pronounced reduction of cardiovascular mortality in MR antagonist–treated patients.1 The underlying mechanisms of these cardiovascular benefits are still debated and are probably diverse. Potential beneficial effects of MR antagonism on extracellular matrix remodeling, arrhythmia susceptibility, coronary flow reserve, cardiovascular inflammation, and vascular function have all been suggested. Indeed, the vasculature has been recently highlighted as a primary target of aldosterone and MR antagonists. MR is expressed in human vascular endothelial cells (ECs) and smooth muscle cells as is the 11β-HSD2 enzyme that allows for selective aldosterone versus cortisol activation of MR. The effects of MR activation on vascular reactivity in healthy humans remains controversial because of conflicting results from clinical studies with many demonstrating a constrictive response and some showing vascular relaxation.2 Discrepancies may be due to differences in the vascular health of study participants as well as differences in study design. However, when patients with underlying cardiovascular diseases are studied, the data are consistent with MR activation promoting increased systemic vascular resistance and reduced forearm blood flow and MR antagonism improving endothelium-dependent vasodilatation, independent of changes in blood pressure. The aggregate of data supports that, in healthy vessels, acute MR activation may evoke endothelium-dependent, NO-mediated vasodilatation, whereas, in the presence of endothelial dysfunction, vascular injury, or high vascular oxidative stress (as in patients with cardiovascular risk factors or heart …

The role of albuminuria as a non‐invasive marker for congestive acutely decompensated chronic heart failure and the spironolactone effect in elderly Portuguese: a non‐randomized trial

Albuminuria is a robust, validated cardiovascular risk factor. It is a simple and widely available test that was shown to be a powerful and independent predictor of prognosis in chronic heart failure. Mineralocorticoid receptor antagonists may reduce the acute and chronic harmful effects of mineralocorticoid receptor activation on the kidney. The objectives of the trial were to compare the effect of spironolactone versus standard acutely decompensated heart failure (ADHF) therapy on albuminuria and to investigate the role of albuminuria as a prognostic marker in patients with ADHF. Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were non-randomly assigned to spironolactone 100 mg/day plus standard ADHF therapy (intervention group) or standard ADHF therapy alone (control group). Patients in control group were older, had higher creatinine and urea levels, and had higher proportion of microalbuminuria (all, P < 0.05). Paired comparison of baseline and day 3 log albuminuria within each group, showed a more pronounced decrease in the intervention group (1.79 ± 0.75 to 1.59 ± 0.67, P = 0.003 vs 1.89 ± 0.70 to 1.79 ± 0.74, P = 0.096). In addition, the proportion of patients with normoalbuminuria increased from baseline to day 3 in spironolactone group (20 (40%) to 27 (54%), P < 001), accordingly the number of patients in the micro and macroalbuminuria groups was reduced. Day 1 albuminuria was positively correlated with day 1 N-terminal pro-brain natriuretic peptide (0.260 [0.105-0.758], P = 0.009). High-dose spironolactone added to standard ADHF therapy is likely to induce a more pronounced albuminuria decrease and a significant reduction in the proportion of micro and macroalbuminuria.

Aldosterone and inflammation

Aldosterone causes tissue inflammation leading to fibrosis and remodeling in the heart, vasculature, and kidney. We summarize recent data regarding the mechanism(s) through which aldosterone stimulates inflammation. Studies elucidate the cell-specific effects of mineralocorticoid receptor activation on inflammatory cell infiltration and adhesion, and highlight the role of the macrophage in the development of vascular collagen deposition and hypertension. Activation of nuclear factor-kappaB in vascular smooth muscle cells involves a complex interplay between the angiotensin subtype 1 (AT1) receptor and the mineralocorticoid receptor. Activation of the mineralocorticoid receptor by aldosterone stimulates an inflammatory phenotype in adipocytes and contributes to insulin resistance by increasing oxidative stress. Mechanistic studies of aldosterone-induced inflammation provide the rationale for an expanded therapeutic role for mineralocorticoid receptor antagonists and aldosterone synthase inhibitors.

Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system

Fifteen years ago Wehling and colleagues showed unequivocal rapid effects of aldosterone, neither mimicked by cortisol nor blocked by spironolactone, and postulated that these nongenomic effects are mediated via a membrane receptor distinct from the classical mineralocorticoid receptor (MR). Several recent studies have challenged this view. Alzamora et al. showed 11β-hydroxysteroid denydrogenase 1 and 2 (11βHSD1, 11βHSD2) expression in human vascular smooth muscle cells, and that aldosterone rapidly raises intracellular pH via sodium–hydrogen exchange; cortisol is without effect and spironolactone does not block the aldosterone response. When, however, 11βHSD activity is blocked by carbenoxolone, cortisol shows agonist effects indistinguishable from aldosterone; in addition, the effect of both aldosterone and cortisol is blocked by the open E-ring, water soluble MR antagonist RU28318. In rabbit cardiomyocytes, aldosterone increases intracellular [Na +] by activating Na +/K +/2Cl − cotransport, with secondary effects on Na +/K + pump activity. Pump current rises ∼10-fold within 15′, is unaffected by actinomycin D or the MR antagonist canrenone, and not elevated by cortisol. Pump current is, however, completely blocked by the open E-ring, water soluble MR antagonist K + canrenoate and stoichometrically by cortisol. PKCɛ agonist peptides (but not PKCα, PKCδ or scrambled PKCɛ peptides) mimic the effect of aldosterone, and PKCɛ antagonist peptides block the effect. Very recently, cortisol has been shown to mimic the effect of aldosterone when cardiomyocyte redox state is altered by the installation of oxidized glutathione (GSSG) via the pipet, paralleling the effect of carbenoxolone on vascular smooth cells and suggesting possible pathophysiologic roles for an always glucocorticoid occupied MR.