Emerging roles for endothelial mineralocorticoid receptor in disease pathogenesis: potential new indications for mineralocorticoid receptor antagonism

1. Introduction

The mineralocorticoid receptor (MR) is a ligand-activated transcription factor, originally identified as a critical regulator of renal electrolyte and fluid homeostasis. MR is primarily activated by aldosterone, produced by the adrenal cortex, and by glucocorticoids in tissues without the cortisol-inactivating enzyme, 11-β hydroxysteroid dehydrogenase-2. Hormone-bound MR regulates transcription of genes involved in sodium reabsorption and potassium excretion in the distal nephron of the kidney(1). MR can be also activated in a hormone-independent manner by angiotensin II and Rac1(2).

Beyond the kidney, MR is expressed in heart, brain, adipose, and immune cells and in the vasculature, including in smooth muscle (SMCs) and endothelial cells (ECs). Substantial progress has been made in understanding the role of EC-MR over the past several decades, implicating EC-MR in the pathogenesis of cardiovascular (CV) and kidney diseases and diabetic complications. Specifically, activation of MR in ECs impairs vasodilation, promotes inflammation and oxidative stress, and drives vascular remodeling (reviewed in (2-4)).

Here, we focus specifically on manuscripts from the past four years and summarize new information regarding the impact of EC-MR on: (1) vascular dysfunction, particularly in the setting of diabetes, (2) acute and chronic kidney disease, and (3) emerging new areas including pulmonary, ocular and blood diseases, reproductive vascular physiology, and cerebrovascular disorders. We emphasize molecular mechanisms and discuss the therapeutic potential of established and emerging MR antagonists (MRAs) in these new clinical applications.

2. EC-MR in vascular function

a. Normal vascular function and the role of EC-MR

The healthy endothelium regulates vasodilation and forms an anti-inflammatory barrier lining all vessels. Prior studies revealed that EC-MR is induced or activated by CV risk factors, including obesity, hyperlipidemia and hypertension, promoting vascular dysfunction. In models of obesity, diabetes or metabolic syndrome, EC-MR contributes to impaired endothelial-dependent dilation, by mechanisms that are sexually dimorphic (reviewed in (5, 6)). In addition, EC-MR drives vascular inflammation by upregulating leukocyte adhesion molecule transcription, fostering atherosclerotic plaque inflammation(7). This section highlights new mechanistic findings using EC-MR deficient mice and novel MRAs to advance understanding of the role of EC-MR in vascular disease.

b. Recent advances in the role of EC-MR in vasomotor dysfunction via endothelial sodium channels

The classical role of MR in renal sodium handling has a vascular parallel. EC-MR regulation of the endothelial sodium channel (EnNaC) has been shown to contribute to endothelial dysfunction in response to metabolic perturbation. Under high-salt conditions, EC-MR activates EnNaC sodium influx, resulting in EC stiffening and compromised vascular relaxation which can further contribute to cardiac and renal dysfunction(8). MR also regulates rapid shear stress-induced EnNaC membrane insertion to increase EC cortical stiffness which is preventable by MR antagonism with spironolactone(9). Similarly, in cold-induced hypertension, endothelium-dependent relaxation is impaired via MR-EnNaC axis and is restored by another MRA, eplerenone, which also lowered blood pressure(10).

c. New findings in EC-MR role in inflammation and atherosclerosis

EC-MR is also recognized to promote vascular inflammation by inducing intercellular adhesion molecule-1 (ICAM1) and other adhesion molecules to recruit leukocytes. Specifically in males, EC-MR drives vascular inflammation by upregulating leukocyte adhesion molecule transcription, fostering atherosclerotic plaque inflammation(7). Mechanisms for the sex-specific effects include progesterone regulation of EC-MR expression and estrogen receptor inhibition of MR signaling (reviewed in (6)). As such, MRAs including eplerenone and spironolactone, have previously been found to attenuate atherosclerosis and plaque inflammation in mouse models (reviewed in (4)). More recently, the non-steroidal MRA esaxerenone was also found to attenuate atherosclerosis progression, decreasing adhesion molecules, macrophage markers, inflammatory cytokines, and oxidative stress mediators, independent of blood pressure or metabolic alterations(11). In human aortic ECs, esaxerenone also blocks tumor necrosis factor-α (TNFα)-induced activation of serum and glucocorticoid-induced protein kinases-1 (SGK1), a downstream effector of MR, implicating SGK1 as a key link between cytokine-driven chronic inflammation and MR signaling(12). In human coronary artery ECs, oxidized low-density lipoprotein induces the MR gene (NR3C2) and enhances NLRP3-driven apoptosis and inflammation, which are reversed by MR silencing(13). In addition, aldosterone impairs EC mitochondrial function via increased mitochondrial reactive oxygen species (ROS)(14). Clinically, the MAGMA trial randomized patients with diabetes and chronic kidney disease (CKD) to spironolactone or placebo and found that MRA attenuated aortic plaque progression in association with serum proteomic changes in oxidative stress, inflammation and leukocyte activation pathways(15), though a specific role for EC-MR was not interrogated hence a role for MR in other cell types (ie smooth muscle, leukocytes) cannot be ruled out. Collectively, these findings support a role for EC-MR in driving atherosclerotic inflammation in preclinical models and position MR antagonism as a potential anti-inflammatory and anti-oxidative strategy in vascular disease, including atherosclerosis complications.

d. New insights into the role of EC-MR in diabetes and metabolic vascular disease

In experimental diabetic models, EC-MR activation impairs endothelial-dependent relaxation. Diabetic mice exhibit increased aldosterone levels and reduced acetylcholine-mediated vasodilation which is prevented with EC-MR knockout. Direct ex vivo aldosterone exposure induces endothelial dysfunction and spironolactone restores it(16). Esaxerenone ameliorates endothelial dysfunction in diabetic mice, suppressing ICAM1 and inflammatory microparticles(17) and enhancing endothelial nitric oxide synthase (eNOS) activity, without altering systemic metabolic, renal, or blood pressure parameters(18), further supporting EC-specific protective effects of MR inhibition in diabetic vascular disease.

EC-MR has similar impact in obesity, even without diabetes. In diet-induced obesity models, EC-MR promotes release of exosomal CD36, disrupting lipid metabolism and inducing skeletal muscle insulin resistance(19). In Western diet-fed female mice, EC-MR deletion prevents aortic fibrosis and stiffness, with reduced endothelial sodium channel activation, oxidative stress and inflammation, and restored endothelial nitric oxide synthase activation, and cardiac diastolic dysfunction, with reduced myocardial oxidative stress and inflammation (reviewed in (5)). In Western diet-fed male mice, EC-MR deletion prevents cardiac dysfunction, with enhanced Akt signaling and reduced cardiac injury compared to females(20), further supporting sex-specific regulatory mechanisms in MR-mediated obesity-related CV diseases.

Together, these studies highlight EC-MR as a critical driver of inflammatory, metabolic, and vasomotor pathways in response to CV risk factors including dyslipidemia, diabetes and obesity, and reinforces the potential of MRAs as promising therapeutic agents to prevent cardiometabolic complications (Figure 1).

Figure 1. Advances in understanding mechanisms of mineralocorticoid receptor (MR)-induced endothelial dysfunction.

Recent literature reveals that endothelial cell (EC) MR induces vasomotor dysfunction, inflammatory and oxidative programs, and pro-fibrotic and remodeling pathways. EnNaC = endothelial sodium channel, eGC = endothelia glycocalyx, eNOS = endothelial nitric oxide synthase, NO = nitric oxide, ROS = reactive oxygen species, O₂⁻• = superoxide ion, Aldo = aldosterone, EndMT = endothelial-to-mesenchymal transition. Created in BioRender.

3. EC-MR in kidney

While MR activity in tubular epithelial cells is established, recent studies reveal a role for vascular MR in driving renal damage and disease. The renal vasculature impacts kidney function by modulating renal blood flow to the glomerulus, which itself is a specialized EC responsible for controlling renal filtration. While early vascular studies focused on MR in SMCs, emerging evidence highlights a broader role for EC-MR in mediating renal vascular dysfunction, inflammation and fibrosis in acute and CKD.

By regulating renal arterial vasoconstriction, vascular MR contributes to renal dysfunction in models of acute kidney injury (AKI) and CKD. In AKI models (ischemia-reperfusion or cyclosporine-A), MRAs mitigate tubular damage and renal dysfunction. This is recapitulated by genetic deletion of SMC-MR via reduced oxidative stress and L-type calcium channel mediated vasoconstriction, whereas EC-MR knockout is not protective(21). In CKD models (subtotal nephrectomy or Munich-Wistar-Fromter), MRAs restore endothelium-dependent vasodilation by attenuating oxidative stress(22, 23), implicating endothelial dysfunction as a CKD driver.

Recent work more directly implicates EC-MR in glomerular injury. The glomerular endothelium relies on vascular endothelial growth factor (VEGF) and the glycocalyx for filtration. As such, VEGF-deficient conditions, including preeclampsia or anti-VEGF cancer therapy, cause renal glomerular endotheliosis and proteinuria. Spironolactone reduces VEGF inhibitor-induced glomerular damage, and this is recapitulated by EC-MR, but not SMC-MR, knockout in mice(24). In streptozotocin-induced diabetic kidney disease, increased glomerular matrix metalloproteinase (MMP) activity coincides with glycocalyx loss, increased permeability and albuminuria, all of which are ameliorated by MRA. The glycocalyx-protective effect of MRAs is reproduced in human glomerular ECs in vitro, and a small randomized trial in diabetic nephropathy patients showed reduced urinary MMP2 activity and albuminuria and preserved glomerular glycocalyx with MRA(25). Serum from dialysis patients increases MR expression, EC stiffness and reduces EC glycocalyx height in primary human ECs, while MRA restores glycocalyx and nitric oxide bioavailability(26). In obesity, aldosterone levels are elevated by adipose-derived leptin(27), and under hyperglycemic conditions, cortisol metabolites excessively activate EC-MR to promote fibrotic signaling(28), further implicating EC-MR over activation in diabetic CKD.

Inflammation and fibrosis further drive CKD. Aldosterone induces pro-inflammatory and pro-fibrotic signaling pathways in the kidney, including CCL5/CCR5 and VEGF-A/TGF-β1 (transforming growth factor-β1), and these effects are mitigated by esaxerenone(29, 30). Similarly, eplerenone inhibits SGK1/TGF-β1-mediated fibrosis in pregnancy-related kidney injury and unilateral ureteral obstruction (UUO)(31), and reduces VEGF-C-mediated lymphangiogenesis and fibrosis in the contralateral kidney after UUO(32). High mobility group box 1 protein, via interaction with receptor for advanced glycation end-products, also contributes to renal inflammation in AKI, which is prevented by MRA(33). Finally, eplerenone attenuates CKD-induced lung inflammation and fibrosis in UUO, suggesting systemic benefits of MR inhibition in renal failure(32).

While a specific role for EC-MR was not tested in all of the models, these findings highlight a growing role for EC-MR in driving acute and CKD by impacting renal blood flow, glomerular health, and renal inflammation and supporting new mechanisms for the therapeutic benefits of MRAs to mitigate renal, vascular, and potentially lung injury associated with CKD.

4. Emerging new roles for EC-MR in disease pathophysiology

a. EC-MR in eye disease

EC-MR has been implicated in ocular disorders of the retina and cornea. A breakthrough study identified EC-MR regulation of potassium channels as a cause of central serous chorioretinopathy, showing that MRA can reverse this vision-threatening disorder in patients(34). A role for EC-MR in angiogenesis has also been examined, with multiple studies showing that activation of MR in ECs suppresses angiogenesis(35) and hence EC-MR KO improves capillary density in the hypertensive heart(36). However, in eye diseases, MR inhibition appears to attenuate vascularization, a process which can interfere with light transmission. In diabetic and hypertensive rats and murine oxygen-induced retinopathy (OIR) models, the non-steroidal MRA, finerenone, significantly attenuates retinal gliosis, vascular leakage and inflammation, associated with reduced infiltration of microglia/macrophages and downregulation of pro-inflammatory mediators ICAM1 and IL-1β. In this OIR model, MR inhibition with finerenone also suppressed VEGF expression and attenuated aberrant neovascularization, with promising outcomes in clinical trials(37). Beyond the retina, MRAs have shown benefits in the cornea. In limbal stem cell deficiency (LSCD), both spironolactone and eplerenone reduce corneal neovascularization and edema, further supporting the anti-angiogenic effect of MRAs in the eye. Spironolactone further promotes nerve regeneration, reduces conjunctivalization and inflammation, and enhances corneal epithelial barrier function. In contrast, MR overexpression disrupts corneal homeostasis, suggesting a pathological role for MR in the ocular surface(38) and therapeutic potential for MRAs in ocular complications of diabetes and other pro-angiogenic disorders of the eye.

b. Hypoxic pulmonary disorders

Recent advances in our understanding of the regulation of the MR gene itself have implications for its role in disease. In addition to regulation of EC-MR by progesterone, the MR gene is induced by the pro-inflammatory transcription factor NFκB and the hypoxia-inducible factor HIF1α(39). As such, MR signaling has recently been implicated in hypoxia-associated pathologies. In a model of obstructive sleep apnea (OSA) induced by chronic intermittent hypoxia, MR expression is increased in coronary ECs and SMCs, contributing to vascular dysfunction that is ameliorated by spironolactone, independent of systemic blood pressure(40). Vascular MR also contributes to pulmonary hypertension (PH) in animal models and PH patients (reviewed in (4, 34)). In one study using the chronic hypoxia-induced PH mouse model, EC-MR deletion significantly attenuated pulmonary vascular remodeling, pulmonary artery pressure and right ventricular dysfunction while this was not observed by SMC-, macrophage-, or fibroblasts-specific MR deletion, and EC-MR deficiency fully reproduced the protective effects of eplerenone(41). In a different study, using the sugen/hypoxia PH model, EC-MR knockout attenuated the right ventricular perivascular fibrosis but did not fully reproduce the benefits of spironolactone, which significantly attenuated pulmonary artery pressure and vascular remodeling(42). These differences may be due to the use of different PH models and MR antagonists, but both studies support EC-MR as a driver of at least some components of PH pathology. These findings nominate EC-MR as a therapeutic target in hypoxia-driven disorders, including PH and OSA.

c. EC-MR in sickle cell disease

Sickle cell disease (SCD) is a genetic disorder impacting hemoglobin, leading to red blood cell occlusion of small vessels, vascular dysfunction and organ damage. SCD complications are associated with elevated endothelin-1 (ET-1), inflammation and oxidative stress, pathways already linked to MR signaling. In a transgenic mouse model of severe SCD, eplerenone improves hematological parameters with reduced plasma ET-1 and red cell potassium channel levels. Eplerenone also decreases cardiac ET-1 and TNF receptor expression and circulating oxidative myeloperoxidase and protein disulfide isomerase (PDI). In ECs, aldosterone-induced PDI activity is reversed by the MRA canrenoic acid, supporting a direct role of EC-MR in redox-mediated vascular inflammation in the SCD model(43). These findings support MR inhibition as a potential therapeutic strategy in SCD, capable of addressing both inflammatory and hematological dysfunction, potentially by inhibiting EC-MR.

d. EC-MR in gut microbiota dysbiosis

The gut microbiome is increasingly recognized in modulating health and disease, particularly in hypertension. As such, the gut-vascular axis has emerged as a novel target of MR signaling in hypertension. In spontaneously hypertensive rats, spironolactone corrects gut dysbiosis, restoring the Firmicutes-to-Bacteroidetes ratio, increasing acetate-producing bacteria and reducing intestinal aerobic microbial populations, which are accompanied by improved colonic epithelial integrity, reduced gut permeability, and attenuated sympathetic activity in the gut. Notably, spironolactone also improves aortic endothelial function and reduces Th17-mediated inflammation, although neuroinflammation in the brain remains unaffected(44). These findings suggest a potential role for MR in mediating gut-induced endothelial pathology in hypertension.

e. EC-MR in skin vasculature and disease

Prior studies have demonstrated a detrimental role for MR activation in skin wound healing in diabetes or glucocorticoid treatment, with beneficial effects of MR inhibition(45-47). The presence of MR in the skin vasculature impacts vascular permeability and inflammation. In rats, acute aldosterone administration increases skin vascular permeability and promotes endothelial exocytosis of the pro-thrombotic protein, von Willebrand factor (vWF). Chronic eplerenone treatment reduces VEGF expression and prevents excessive vWF release without altering skin histology or gene expression profiles(48). These data, added to the prior literature, suggest that MR activation contributes to skin microvascular dysfunction, with implications for topical MR inhibition to have benefits in diseases involving vascular leak, skin edema, and wound healing(45-48).

f. EC-MR in placental and uterine function

EC-MR also plays a significant role in reproductive vascular physiology, with implications for both maternal and fetal health(49, 50). In a mouse model of placental ischemia-induced preeclampsia, EC-MR deletion attenuates hypertension and fetal growth restriction(49). Further, studies in macaque monkeys reveals menstrual cycle–dependent localization of MR in the endometrium(50). MR localizes to ECs during the proliferative phase and to stromal cells during the secretory phase, paralleling changes in plasminogen activators, suggesting a role for MR in endometrial vascular remodeling that is regulated by sex steroid cycling. The anti-mineralocorticoid properties of certain progestins may account for reduced uterine bleeding, implicating MR-activation in menstrual cycle regulation and abnormal bleeding(50).

g. MR circuits in the brain and potential role in bone and cognitive disorders

MR also influences cerebrovascular function. Prior studies using mice with EC-MR deletion reveal a role in hypertensive remodeling of cerebral arteries which leads to reduced cerebral perfusion contributes to adverse outcomes in stroke and dementia models(51). A recent study shows that, in chronic hypertension mouse models, impaired endothelial Kir2.1 channel activity disrupts functional hyperemia, the ability to increase blood flow to active brain regions, and contributes to small vessel disease and dementia. Although both the angiotensin receptor inhibitor losartan and the calcium-channel blocker amlodipine reduce blood pressure, only amlodipine preserves functional hyperemia. This difference is linked to losartan-induced aldosterone breakthrough, which increases MR activation and endothelial dysfunction. Importantly, co-treatment with losartan and eplerenone restores functional hyperemia, emphasizing a role for MR in cerebral endothelial dysfunction and MRAs to prevent small vessel disease and cognitive impairment(52). Additionally, in glucocorticoid-induced osteonecrosis of the femoral head, glucocorticoids disrupt glucocorticoid receptor (GR)-MR balance within the hypothalamic paraventricular nucleus, suppressing MR activity and reducing sympathetic outflow. This imbalance results in EC apoptosis and vascular rarefaction in the femoral head. Restoration of MR signaling via GR inhibition in the brain reinstates sympathetic tone and protects bone vascular integrity(53).

h. EC-MR in COVID-19

The COVID-19 pandemic has shed light on the pathological role of MR in viral-mediated vascular injury. SARS-CoV-2 enters cells, including ECs, via the angiotensin-converting enzyme-2 (ACE2) protein. SARS-CoV-2 infection induces ATP release through cortisol-mediated MR activation in ACE2-expressing cells, contributing to hallmark symptoms such as anosmia, cough, and vascular leakage via endothelial dysfunction. This concept prompted a clinical trial showing that spironolactone with low-dose dexamethasone significantly improves respiratory outcomes compared to high-dose dexamethasone alone, without adverse effects(54). Furthermore, MR activation exacerbates SARS-CoV-2 spike protein-induced endothelial expression of plasminogen activator inhibitor-1 and leukocyte adhesion molecules. This is particularly apparent in men and is mediated by androgen and TNFα pathways. Spironolactone suppresses spike protein-induced monocyte adhesion and endothelial activation in vitro. Elevated endothelial injury markers (VCAM-1 and E-Selectin) in male patients suggests sex-specific pro-inflammatory effects of EC-MR(55). These findings establish EC-MR as a mediator of COVID-19-associated vascular injury and support further exploration of MR blockade as a potential therapeutic strategy for acute and long-term complications(54, 55).

i. EC-MR in cardiac endothelium may contribute to cardiac disease

Finally, these myriad roles for EC-MR can also contribute to cardiac dysfunction in response to stress. Recent integrative epigenomic analyses reveal that endothelial enhancers activated in heart failure, hypertension, and diabetes are enriched with MR-binding motifs. The study revealed that MR orchestrates disease-specific chromatin remodeling in cardiac ECs, influencing gene expression programs central to inflammation, fibrosis, and vascular dysfunction(56). These findings support a growing body of literature implicating EC-MR, in addition to, or perhaps more than, MR in the cardiomyocyte, in driving heart failure (reviewed in (57)).

5. Conclusion and future perspectives

Across renal, cardiovascular, and metabolic systems and increasingly in the eye, lung, skin, reproductive, and neurovascular beds, EC-MR emerges as a unifying driver of vascular dysfunction. The recent literature converges on a mechanistic triad by which EC-MR promotes disease through; (i) impaired vascular tone via EnNaC activation, eNOS dysregulation and glycocalyx damage, (ii) enhanced inflammation mediated by SGK1, NLRP3, mitochondrial ROS, and induction of adhesion molecules, and (iii) pro-fibrotic remodeling involving TGF-β and EndMT (Figure 1). These pathways explain the consistent benefits of traditional (spironolactone, eplerenone) and novel MRAs (finerenone, esaxerenone) on EC function leading to improved outcomes across models of kidney injury, atherosclerosis, pulmonary hypertension, diabetes, obesity, and even hypoxia- or virus-induced vascular injury (Figure 2). At the same time, cell type, sex, metabolic state and environmental exposures can shift the impact of EC-MR effects, underscoring the need for further investigation to drive precision targeting. Therapeutically, the field is at an inflection point. Established MRAs increasingly demonstrate endothelial and multi-organ advantages that extend beyond natriuresis and blood pressure control, positioning EC-MR as a tractable target for disease modification, and novel specific and potent MRAs and aldosterone-synthase inhibitors are rapidly being developed. Yet several knowledge gaps limit translation including; (1) spatiotemporal dynamics of EC-MR signaling during acute versus chronic diseases, (2) determinants of sex-specific responses, and (3) validated endothelial biomarkers that can serve as pharmacodynamic readouts and surrogate endpoints in trials.

Figure 2. Diverse new disease targets for MR antagonism.

New data reveals beneficial effects of traditional and novel MR antagonists (spironolactone, eplerenone, finerenone and esaxerenone) on EC function resulting in improved outcomes in diabetes- and obesity-related vascular disease, acute and chronic kidney injury, and expanded indications to diseases across multiple organs including the brain, eye, skin, gut, blood, lung and heart. AKI = acute kidney injury, CKD = chronic kidney disease, OSA = obstructive sleep apnea, PH = pulmonary hypertension. Created in BioRender.

In summary, MR in vascular ECs coordinates vascular tone, inflammation, oxidative stress and fibrosis across multiple organs. Targeting EC-MR can convert incremental advances into tremendous benefit for kidney, cardiovascular, metabolic, and a host of additional emerging diseases.