Glucocorticoid Resistance-Induced Inflammation Drives Cardiovascular-Kidney-Metabolic (CKM) Syndrome Pathophysiology

Abstract

Prolonged activation of the hypothalamic–pituitary–adrenal (HPA) axis results in an excessive secretion of the glucocorticoid hormone cortisol, which contributes to weight gain, increased appetite, and inflammation. Glucocorticoids are essential in regulating stress responses and suppressing immune functions. They bind to the glucocorticoid receptor (GR) and influence gene expression through transcriptional mechanisms. Sustained elevation of glucocorticoid levels may lead to glucocorticoid resistance, thereby contributing to inflammation, adiposity, and insulin resistance, which negatively impact the hepatic, cardiovascular, and renal systems. This condition is referred to as the Cardiovascular-Kidney-Metabolic (CKM) Syndrome. The notable pathologies associated with glucocorticoid resistance and CKM Syndrome are discussed, with particular emphasis on CKM staging and potential therapeutic strategies for individuals with cardiometabolic dysfunction.

THE LINK BETWEEN GLUCOCORTICOID RESISTANCE AND CKM SYNDROME

A global epidemic of metabolic dysfunction has emerged as a consequence of the widespread prevalence of individuals who are overweight or obese. This excess adiposity affects nearly all bodily systems, leading to fat accumulation even in tissues traditionally not associated with lipid storage, such as the liver. Recent investigations indicate that Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (see Glossary) affects approximately one in three adults and 1.6 billion individuals worldwide, serving as a precursor to other metabolic conditions, including hypertriglyceridemia, insulin resistance, and glucose intolerance [1, 2]. If untreated, MASLD may progress to the irreversible form known as Metabolic Dysfunction-Associated Steatohepatitis (MASH), characterized by liver fibrosis and inflammation, and it may potentially advance to hepatocarcinoma (HCC) [1, 3–6]. Chronic stressors, whether psychological or physiological, can induce sustained activation of the hypothalamic–pituitary–adrenal (HPA) axis [7]. Excessive activation of this axis or localized cortisol accumulation can result in weight gain, increased appetite, and inflammation, thereby significantly affecting the cardiovascular and renal systems [7]. Over time, tissues may develop glucocorticoid resistance, disrupting normal cortisol feedback mechanisms and fostering systemic inflammation [8]. Predominantly, glucocorticoid resistance predisposes to the development of inflammatory and metabolic disorders, kidney pathologies, and cardiovascular disease (CVD) [7, 9–11]. The occurrence of glucocorticoid resistance facilitates the progression of proinflammatory pathways [7], with inflammation being a critical factor in the emergence of the Cardiovascular-Kidney-Metabolic (CKM) syndrome (Figure 1) [12, 13].

Figure 1.

Pathological conditions shared between glucocorticoid resistance and CKM syndrome.

Glucocorticoid resistance impacts multiple tissues, including the liver, cardiovascular system, pancreas, kidneys, and adipose tissue. In the liver, it is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), which is characterized by inflammation and elevated triglyceride levels. Adipose tissue dysfunction involves visceral obesity, chronic inflammation, and ectopic fat buildup. Pancreatic issues include type 2 diabetes, glucose intolerance, and insulin resistance. Cardiovascular problems such as coronary artery calcification, hypertension, and heart failure are also associated. Renal effects can lead to kidney disease and, in severe cases, kidney failure. Overall, these interconnected conditions underscore the systemic nature of glucocorticoid resistance and its vital role in the development of metabolic, cardiovascular, and renal dysfunction, collectively constituting the cardiovascular-kidney-metabolic (CKM) syndrome.

The American Heart Association’s presidential advisory officially defines CKM syndrome as a connected, systemic disorder involving the metabolic, kidney, and cardiovascular systems [14]. It results from pathophysiological interactions among conditions such as obesity, type 2 diabetes, chronic kidney disease (CKD), and CVD, leading to multi-organ dysfunction and a significantly increased risk of adverse cardiovascular outcomes. The CKM staging system indicates a progressive risk spectrum with five stages (0–4) (shown in Table 1), which correspond to increasing pathophysiology and CVD risk [14]. The connection between CKM health and glucocorticoid resistance may start early with excessive or dysfunctional fat accumulation that worsens over time [15]. Glucocorticoid resistance affects adipose lipolysis, glucose uptake in fat and muscle, and hepatic glucose production via gluconeogenesis, further driving insulin resistance and dyslipidemia [7], which are key elements of CKM stage 1 (metabolic dysfunction associated). Core features of CKM syndrome and glucocorticoid resistance include low-grade inflammation, which promotes insulin resistance, obesity, endothelial dysfunction, atherosclerosis, and a pathological inflammatory-metabolic dysfunction [7, 13, 16]. CKM pathophysiology highlights that abnormalities in stress hormone signaling, including glucocorticoids, intersect with oxidative stress, mitochondrial dysfunction, and insulin resistance as common mechanisms across the CKM spectrum [15]. In this context, we examine the mechanisms underlying glucocorticoid resistance as a primary factor in the pathophysiology of CKM, the regulatory elements that influence glucocorticoid levels, the translational significance of glucocorticoid resistance, and prospective pharmacological targets to improve glucocorticoid and insulin sensitivity in CKM Syndrome.

Table 1:

Stages of the Cardiovascular-Kidney-Metabolic (CKM) Syndrome.

AMERICAN HEART ASSOCIATION CRITERIA FOR THE FIVE STAGES OF CKM SYNDROME
CKM Stage	CKM Risk Factors and Other Characteristics	Diagnostic and Testing Parameters
0	No risk factors for CKM identified.	Individuals with a normal body mass index (BMI) and waist circumference, who also have normal blood sugar levels, blood pressure, lipid profiles, and show no signs of CKD or subclinical or clinical cardiovascular disease.
1	Metabolic dysfunction associated with excessive or dysfunctional adiposity.	People who are overweight or have obesity (BMI of ≥25 kg/m2, or ≥23 kg/m2 for those of Asian descent), abdominal obesity, or dysfunctional adipose tissue, and who do not have other metabolic risk factors or CKD. Additional indicators include a waist circumference greater than 88/102 cm for women/men (or ≥80/90 cm if of Asian descent), fasting blood glucose between 100 and 124 mg/dL, or an HbA1c from 5.7% to 6.4%.
2	Metabolic risk factors and chronic kidney disease (CKD).	Individuals with metabolic risk factors such as hypertriglyceridemia (≥135 mg/dL), hypertension, Metabolic Syndrome (MetS), insulin-resistant diabetes, or CKD.
3	Subclinical cardiovascular disease (CVD) or advanced high-risk CKD / high estimated cardiovascular risk.	Subclinical heart failure or subclinical atherosclerotic cardiovascular disease (ASCVD) manifests in individuals presenting with excess or dysfunctional adiposity, additional metabolic risk factors, or CKD. The diagnosis of subclinical ASCVD primarily depends on the detection of coronary artery calcification. Subclinical heart failure is identified through elevated cardiac biomarkers indicative of an increased risk of developing heart failure. Risk factors associated with subclinical cardiovascular disease (CVD) include advanced stages of CKD and a high 10-year CVD risk assessment.
4	Clinical CVD with or without renal failure.	Clinical CVD encompasses conditions such as coronary heart disease, heart failure, stroke, peripheral artery disease, and atrial fibrillation. It occurs in individuals with excess or dysfunctional adiposity, other CKM risk factors, or more advanced stages of CKD.

^*The criteria above were adapted from [14].

PHYSIOLOGICAL OUTCOMES OF GLUCOCORTICOID RESISTANCE

Glucocorticoid Signaling Mechanisms

GR predominantly exists in two isoforms: GRα, which binds glucocorticoids, and GRβ, which lacks glucocorticoid-binding capacity and functions as a dominant-negative regulator of GRα [7, 17] (see Box 1). Consequently, GRβ attenuates glucocorticoid signaling by inhibiting GRα [18, 19], thereby contributing to glucocorticoid resistance, as depicted in Figure 2. Recent research has advanced the understanding of GRα function, demonstrating that ligand binding promotes dimerization and higher-order oligomerization, possibly into tetramers, which are essential for optimal transcriptional activity and chromatin interaction [20]. GRα recruits coactivators such as p300/CBP and the mediator complex; ligand-specific engagement of these coregulator proteins modulates transcriptional outcomes [21, 22]. Crosstalk with lineage-specific transcription factors, including LXR, PPARα, and CLOCK, facilitates precise, tissue-specific transcriptional responses [23, 24]. Simultaneously, non-genomic GR signaling has emerged as a significant regulator of cellular metabolism, impacting mitochondrial function and cytoplasmic signaling pathways independently of direct DNA interaction [25]. Additional mechanisms are also involved and will be discussed in subsequent sections. Factors such as chronic stress and mutations in the NR3C1 gene significantly elevate cortisol levels, thereby altering glucocorticoid sensitivity and contributing to CKM-related health issues [7], especially affecting the cardiovascular and renal systems.

Box 1. Signaling Mechanisms of the Glucocorticoid Receptors.

The NR3C1 gene encodes two primary isoforms (Figure I): GRα, which actively binds glucocorticoids, and the GRβ isoform, characterized by a truncated ligand-binding domain, absence of a known ligand, and the capacity to inhibit GRα function [13]. These receptor isoforms share conserved structural domains typical of nuclear receptors, including the N-terminal, DNA-binding (DBD), hinge region, and C-terminal domains [15]. The N-terminal region encompasses the activation factor-1 (AF-1) domain, where phosphorylation by phosphorylation modulates the transcriptional activity of GR proteins. The C-terminal region contains the ligand-binding domain (LBD) and the activation factor-2 (AF-2) domain, which interact with coregulator proteins to regulate gene transcription [15]. The ligand-binding domain is essential for canonical GRα signaling. In contrast, GRβ differs from GRα by lacking helix 12 [2], which is critical for hormone binding in GRα; consequently, GRβ cannot bind conventional glucocorticoids [2], and further research is required to identify potential specific ligands for GRβ. The canonical signaling pathway of GRα involves several key steps: initially, glucocorticoids bind to GRα in the cytoplasm; subsequently, the hormone-bound receptor translocates to the nucleus, where it binds to glucocorticoid response elements (GREs) located in the promoters of target genes (Figure I). These GREs are palindromic sequences recognized by the DNA-binding domain of all GR isoforms, facilitating homodimerization. Upon homodimerization, GRα recruits histone acetyltransferase (HAT) proteins, thereby initiating gene transcription [15]. An important mechanism contributing to glucocorticoid resistance involves increased production of GRβ, which antagonizes GRα by heterodimerizing with it at GREs [2, 19, 91]. When heterodimerized, GRβ recruits histone deacetylases (HDACs), leading to suppression of gene transcription. The recruitment of HDAC by GRβ results in diminished sensitivity to glucocorticoids, contributing to glucocorticoid resistance. A decreased GRα:GRβ ratio indicates potential glucocorticoid resistance, as elevated levels of the dominant-negative GRβ isoform inhibit GRα activity, thereby reducing glucocorticoid-mediated transcriptional signaling [91].

Whether produced endogenously or administered exogenously, excessive, chronic glucocorticoid levels compromise glucocorticoid signaling. Exogenous glucocorticoids can cause drug-induced glucocorticoid resistance, similar to that associated with an overactive HPA axis, which also causes inflammation, increased adiposity, and cardiovascular and metabolic dysfunction [7]. Factors such as polymorphisms in the NR3C1 gene and the presence of inhibitory proteins bound to the GR heterocomplex influence glucocorticoid sensitivity.

Figure 2.

Pathways and Mechanisms that Initiate Glucocorticoid Resistance.

Key intracellular signaling components of glucocorticoid resistance involve several interacting pathways. (1) FKBP51-HSP90 forms a chaperone complex that blocks GRα (Glucocorticoid Receptor alpha) translocation to the nucleus until a ligand binds, while the FKBP51-PHLPP complex inhibits AKT phosphorylation, altering downstream signaling. (2) Glucocorticoids (GCs) bind to and activate GRα, enabling it to function as a transcription factor. (3) GRα then translocates to the nucleus, where it binds to (4) GREs (Glucocorticoid Response Elements) on DNA to regulate gene transcription. In contrast, (5) GRβ (Glucocorticoid Receptor beta), an inactive isoform of the receptor, is activated by inflammatory signaling through (6) NF-κB, which increases GRβ levels and its binding to GREs, initiates the transcription of adiposity-related and proinflammatory genes, and inhibits GRα activity. NF-κB, a proinflammatory transcription factor, also interacts with and inhibits GRα via tethering. Additionally, AKT phosphorylates the NF-κB p65 subunit at serine 534, enhancing its transactivation, nuclear translocation, and activation of GRβ. (7) MR (Mineralocorticoid Receptor) is activated by excessive glucocorticoid levels, promoting proinflammatory pathways. The MR translocates to the nucleus and binds DNA to regulate gene expression, further contributing to glucocorticoid resistance.

Glucocorticoids, such as cortisol, are produced as part of the body’s natural stress response. These steroid hormones [21] generated by the adrenal cortex [7] are regulated via the HPA axis [26]. They follow a daily circadian pattern and are essential for maintaining homeostasis and supporting vital physiological functions during stress [27] and immunosuppression [26]. Today, they are among the most frequently prescribed anti-inflammatory drugs. However, prolonged use can reduce glucocorticoid efficacy, potentially due to impaired GRα signaling [7]. Even without external glucocorticoid treatment, some individuals may develop glucocorticoid resistance due to continuous cortisol overproduction. Local glucocorticoid synthesis is regulated by the isozymes 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 11β-HSD2). These enzymes produce glucocorticoids locally and may affect resistance or sensitivity to these hormones, as discussed below.

Glucocorticoid resistance can significantly impact various tissues and overall health. Skeletal muscle is particularly sensitive to glucocorticoid signals, which can cause tissue wasting (atrophy) [28]. Elevated glucocorticoid levels promote protein breakdown and inhibit synthesis, leading to decreased muscle mass [29]. In some instances, the effects of glucocorticoid resistance might even be advantageous. For example, studies have shown that overexpressing GRβ in mouse myocytes via a lentiviral vector greatly increased myoblast proliferation, myotube size, and muscle-regulating gene expression [30]. Therefore, inhibiting glucocorticoid activity in skeletal muscle could have beneficial outcomes. Similar to their effects on muscle, glucocorticoids also impair bone density and bone formation, and resistance to them worsens both bone breakdown and formation, increasing osteoporosis and fracture risk due to increased bone fat [31]. The influence of glucocorticoids on muscle and bone highlights situations in which glucocorticoid resistance may be beneficial. Conversely, in tissues such as the liver, adipose tissue, and the cardiovascular and renal systems, glucocorticoid resistance may contribute to the development of CKM syndrome, as discussed further below.

Inflammatory Mechanisms in Glucocorticoid Resistance

Glucocorticoids usually suppress immune responses and inflammation. However, long-term use can lead to reduced suppression, potentially increasing immune cell proliferation and inflammation. Glucocorticoid signaling affects various immune cells, including B cells, T cells, macrophages, dendritic cells, and natural killer (NK) cells. When glucocorticoid resistance develops, their levels often rise [32, 33]. One study showed that B cells and their progenitors in acute lymphoblastic leukemia (BCP-ALL) have high levels of GR proteins [34]. Notably, this research measured total GR protein levels rather than specific isoforms, a focus for future studies. Interestingly, dasatinib, a multi-kinase inhibitor, can counteract glucocorticoid resistance, leading to increased cell death in vitro, decreased leukemic burden, and better survival in an in vivo xenograft model [34]. These findings suggest some medications might overcome glucocorticoid resistance in certain diseases. It has also been observed that glucocorticoid-resistant BCP-ALL with a poor prognosis exhibits the highest overall GR expression and elevated levels of signaling mediators, including cyclin A, cyclin B, NF-κB, and c-myc, which are normally repressed [34]. In resistant B-ALL, phospholipase C (PLC)-mediated survival pathways become abnormally activated through CXCR4 signaling [35]. In T-ALL cells, increased MEK/ERK signaling has been linked to glucocorticoid resistance [36]. Moreover, upregulation of the interleukin-7 receptor (IL7-R) in T-ALL confers resistance by activating pathways such as phosphoinositide 3-kinase (PI3K)-AKT and Janus kinase (JAK)-STAT, which promote cell proliferation and counteract the cell death typically induced by glucocorticoids [36]. Much remains to be learned about immune health in glucocorticoid resistance and CKM syndrome.

Metabolic Dysfunction Caused by Glucocorticoid Resistance

Glucocorticoid Resistance in Adipose Tissue and Obesity

Similar to other tissues throughout the human body, adipose tissue is affected by glucocorticoids. The signaling pathways mediated by GRα in adipose tissue during acute glucocorticoid administration include lipolysis, fatty acid liberation, and glycerol release from adipocytes [37]. However, with long-term glucocorticoid therapy, increases in adiposity and lipogenesis are observed, potentially due to glucocorticoid resistance and inflammatory activation (Figure 2). It is well established that prolonged glucocorticoid exposure promotes abdominal obesity and inflammation [38, 39]. Compared with lean mice, obese mice treated with dexamethasone exhibited more severe MASLD, despite significant reductions in body weight, white adipose tissue mass, and total fat mass [30]. Furthermore, these obese mice exhibited significantly higher fasting glucose levels than the lean group under identical conditions. These findings suggest that the interaction of chronically elevated glucocorticoids and obesity contributes to the exacerbation and progression of metabolic dysfunction associated with CKM stages 1 and 2 (Table 1).

Mice with total GR (both GR isoforms) knocked out in adipose tissue did not demonstrate dexamethasone-induced [40] or corticosterone-induced [41] glucose intolerance, as assessed through the glucose tolerance test (GTT). Nevertheless, none of the mice, including the floxed controls with an intact GR, showed any effect on the dexamethasone-induced reduction in adipocyte size [40], a phenomenon that has been extensively documented. This observation may suggest that dexamethasone exerts its effects in tissues beyond adipose tissue, such as the liver, which is known to influence insulin sensitivity by modulating insulin clearance [1, 42, 43]. A limitation of the total GR knockout model is that it cannot be determined which isoform mediates the chronic effects of glucocorticoids. Overexpression of GRβ in mice on a standard chow diet for 5 days has been shown to induce hepatic lipid accumulation and inflammation at levels characteristic of MASLD [44]. The GRβ-specific knockout mice, in which GRα remained expressed, demonstrated that GRβ enhances PPARγ-mediated adipogenesis [45]. It has also been demonstrated that GR binds to the PPARγ promoter, thereby increasing its expression [46], and that it stimulates NF-κB phosphorylation [44], which may elucidate its role in adiposity and inflammation (Figure 2). GRβ-induced glucocorticoid resistance remodels hepatic lipids, resulting in increased monoacylglycerides [47], which facilitate the production of eicosanoids and prostaglandins, pivotal mediators of inflammation. Additionally, these mice exhibited elevated expression levels of genes associated with inflammation. PPARγ agonists such as pioglitazone and rosiglitazone [48] have been shown to inhibit dexamethasone-induced lipolysis and insulin resistance in primary rat adipocytes in vitro and in rat models in vivo [49]. These findings suggest that PPARγ agonists may have therapeutic potential in managing glucocorticoid resistance, particularly given their ability to enhance insulin sensitivity and exert anti-inflammatory effects [48]. Elevated levels of GRβ, which are correlated with glucocorticoid resistance and inflammation, augment PPARγ signaling, thereby contributing to increased adiposity, hepatic lipid accumulation (steatosis), and metabolic dysfunction. Nonetheless, further research is necessary to elucidate the functions of specific GR isoforms in the context of CKM Syndrome.

Preclinical investigations in rat models indicate that males exhibit heightened susceptibility to cortisol-induced augmentations in visceral adiposity, due to elevated GR protein levels across all adipose depots following two weeks of corticosterone treatment. Conversely, females subjected to the same treatment did not show variations in GR protein concentrations [50]. These findings suggest that sex hormones may also modulate sensitivity to glucocorticoids. CKM syndrome manifests sex differences in prevalence and cardiovascular outcomes [51]. Furthermore, both GR and MR functionalities are influenced by sex steroids, as elaborated in greater detail [7]. Consequently, sex as a biological variable warrants consideration in the contexts of CKM syndrome and glucocorticoid resistance conditions. A comprehensive understanding of the molecular relationship between GR isoform signaling and adipose tissue inflammation may facilitate the development of therapeutic interventions to reduce local and systemic inflammation, enhance insulin sensitivity, and improve overall metabolic health, with due consideration of sex differences.

Hepatic Function and Glucocorticoid Resistance

A major role of glucocorticoid signaling in the liver is to promote energy balance by regulating gluconeogenesis to supply glucose during fasting or stress-related flight-or-fight responses [52]. Chronic exposure to glucocorticoids raises plasma glucose levels, leading to hyperglycemia and insulin resistance [52]. Liver-specific inactivation of GR using an antisense oligonucleotide against it in mice, and hepatocyte-specific GR knockout (KO) in rats, decreases fasting hyperglycemia, fasting insulin levels, and hepatic glucose output, thereby countering insulin resistance diabetes [53, 54]. Short-term activation of GRα promotes lipolysis [55], whereas prolonged exposure promotes lipogenesis [56], likely due to high GRβ levels [44].

As demonstrated by the adenovirus overexpression of GRβ (GRβ-Ad) in the liver of mice on a normal chow diet for five days, de novo lipogenesis and inflammatory pathways are also heightened in the glucocorticoid-resistant liver [44, 47]. At the same time, PPARα fat-burning pathways were reduced in a glucocorticoid-resistant state [44]. This was exemplified by reduced levels of PPARα and fibroblast growth factor 21 (FGF21) in the livers of GRβ-Ad mice, thereby hindering activation of the β-oxidation pathway [44]. Lipidomic analysis of glucocorticoid-resistant livers showed significantly higher levels of monoacylglycerides [47], a lipid used for the generation of prostaglandins that is associated with inflammation and cardiovascular dysfunction [57].

Glucocorticoid Resistance and Effects on the Cardiovascular and Renal Systems

Glucocorticoid resistance can significantly impact cardiovascular health, as high cortisol levels bind to the mineralocorticoid receptor (MR) (Figure 2). Many tissues co-express both MR and GR, including the heart, kidney, adipose tissue, hippocampus, and liver (details on MR and GR tissue distribution and ligand selectivity are further explained in [17]). The ratio of GRα to MR and their binding states may influence the balance between anti-inflammatory and pro-inflammatory gene expression. In glucocorticoid resistance, where functional GRα is reduced, and MR is overactivated by excess cortisol, this shift might be a key molecular mechanism underlying features of CKM syndrome, especially in CKM Stages 3 and 4 (Table 1). This resistance often presents with hypokalemia and salt-sensitive hypertension, caused by MR-driven transcription and the sympathetic nervous system [58]. Altered GRα binding to glucocorticoids has been observed in hypertensive patients, especially those with low-renin hypertension, indicating improper cortisol binding to MR [59]. Studies in GR mutant rats showed salt-sensitive hypertension linked to increased soluble epoxide hydrolase (sEH), which decreases vasodilatory fatty acids that protect against salt-sensitive hypertension [60]. It is advisable to consider strategies to limit excessive cortisol-induced MR activation when managing cardiovascular diseases associated with glucocorticoid resistance.

Overactivation of MR is an emerging pathway in CKM syndrome (Figure 2). MR activation, caused by aldosterone or elevated cortisol levels, impacts the heart and blood vessels, promoting inflammation. Excess glucocorticoids can increase cardiac fibrosis through MR-mediated oxidative stress and inflammation [61]. In blood vessels, MR influences ion channels, oxidative stress, stiffness, and blood pressure [62]. Clinical studies have highlighted the significance of MR activation in response to elevated cortisol levels due to glucocorticoid resistance in CKM syndrome. In the FIDELIO-DKD trial, Finerenone, a nonsteroidal, selective MR antagonist, reduced the risk of CKD progression and cardiovascular events in patients with CKD and insulin-resistant diabetes [63]. Similar cardiovascular benefits of Finerenone were observed in the FIGARO-DKD trial [64]. These findings suggest MR activation plays a key role in CKM development and that MR antagonists may offer promising therapeutic options.

ENZYMATIC PRODUCTION OF GLUCOCORTICOIDS

11βHSD Isozymes and Their Roles in Metabolic Dysfunction

People with obesity exhibited elevated 11β-HSD1 expression and activity in adipose tissue [65]. Conversely, another investigation showed no significant differences in 11β-HSD1 expression between obese individuals with metabolic syndrome and those without [66]. RNA sequencing data comparing metabolically unhealthy obese individuals with their healthy counterparts showed no significant difference in 11β-HSD2 expression between the two groups [67]. There is a dimorphic mechanism in which 11β-HSD1 modulates local glucocorticoid effects and promotes insulin resistance, visceral fat accumulation, dyslipidemia, MASLD, and fibrosis [68]. 11β-HSD1 activity increased local cortisol levels, mimicking the high cortisol levels observed in subcutaneous adipose tissue in Cushing’s disease [7]. In CKD, 11β-HSD1 mRNA, protein, and activity levels were elevated and associated with intrahepatic glucocorticoid excess, increased hepatic gluconeogenesis and lipogenesis, and insulin resistance [69]. Women with PCOS exhibited higher saturated fatty acid levels within their adipose depots and increased 11β-HSD1 mRNA and protein expression [70]. Lipid metabolism is further influenced by augmented 11β-HSD1 signaling. Another study demonstrated that selective inhibition of 11β-HSD1 activates AMPK signaling and energy-dependent pathways, thereby reducing lipid accumulation [71].

Accumulating evidence suggests that the expression or activity of 11β-HSD2 may be diminished in metabolic tissues. This reduction facilitates increased localized cortisol effects, and elevated levels can bind to MR [7], thereby contributing to hypertension, CVD, and renal pathology [72]. Mechanistically, 11β-HSD2 inactivates 11-hydroxysteroids in the kidney, preventing their binding to GR [17]; therefore, the loss of 11β-HSD2 activity results in elevated steroid levels and subsequent overactivation of MR, leading to hypertension [73]. It has been hypothesized that CKD is associated with 11β-HSD2 deficiency. However, it has been shown that, in adult patients, 11β-HSD2 deficiency is present across a spectrum of renal function [74].

The Impact of 11βHSD Isozymes on the Cardiovascular and Renal Systems

The enzymes 11β-HSD1 and 11β-HSD2 catalyze the interconversion of cortisol and cortisone [7], a crucial process in kidney function, as high cortisol levels can activate MR [17, 75]. Specifically, 11β-HSD1 negatively affects cardiovascular health by promoting adipose tissue accumulation. Overexpression of this enzyme in fat tissue has been linked to metabolic dysfunction and hypertension. These insights have led to the development of 11β-HSD1 inhibitors as potential treatments for hypertension. Studies show that administering an 11β-HSD1 inhibitor lowers blood pressure across various rat models of glucocorticoid-induced hypertension, regardless of its effects on insulin sensitivity [76].

Although some evidence suggests that changes in 11β-HSD1 may lead to hypertension through indirect pathways, stronger evidence indicates that reduced renal expression of 11β-HSD2 promotes hypertension by activating MR via cortisone, as MR binds both cortisone and cortisol [17]. Studies with 11β-HSD2-deficient mice and rats have shown that loss of 11β-HSD2 causes a low-renin hypertension that mimics the Syndrome of Apparent Mineralocorticoid Excess (SAME) [77]. While blood pressure initially rises due to volume retention, research indicates that long-term increases in renal vascular resistance might sustain the elevated blood pressure seen in 11β-HSD2 deficiency [78]. Additional studies using kidney-specific 11β-HSD2-deficient mice have found that renal loss of 11β-HSD2 leads to hypertension by overactivating MR, a process that can be countered by treatments such as amiloride and hydrochlorothiazide [79].

Glucocorticoids are integral to regulating 11β-HSD2 gene expression and activating MR in the renal system. Excessive prenatal exposure to glucocorticoids has been shown to suppress renal 11β-HSD2 levels and induce salt-sensitive hypertension in adult rats [80]. Furthermore, the relationship between glucocorticoids and MR activation has been corroborated by studies in mice deficient in aldosterone synthesis due to deletion of the aldosterone synthase (AS) gene. AS-deficient mice exhibit hyperkalemia and natriuresis in response to eplerenone, thereby confirming that glucocorticoids activate MR, a phenomenon that likely occurs during glucocorticoid resistance.

MOLECULAR MECHANISMS AND GENETIC CAUSES OF GLUCOCORTICOID RESISTANCE

Factors that Mediate Glucocorticoid Signaling

Glucocorticoids, including synthetic forms like prednisone and dexamethasone, are among the most common medications prescribed [7]. They activate the GRα isoform (Box 1), and, due to its negative self-regulatory feedback loop, prolonged exogenous glucocorticoid use can lead to resistance and other side effects [7]. Various molecular mechanisms underlie glucocorticoid resistance, summarized in Table 2 and shown in Figure 2. These involve changes in the expression or activity of proteins that regulate GR-mediated transcription. Notably, GR protein levels decrease through a negative feedback mechanism involving the HPA axis and proinflammatory cytokines [81]. GRβ acts as a dominant-negative regulator of GRα, providing negative feedback. In a study on gestational diabetes, it was indicated that GRβ directly regulates PPARγ2 expression at its promoter [46]. These findings imply that GRβ selectively inhibits GRα-mediated functions, such as lipolysis and fat breakdown, thereby favoring fat storage and lipogenesis.

Table 2.

Protein signaling mechanisms leading to glucocorticoid resistance.

Causes of Glucocorticoid Resistance	Summary	Ref
GRβ Increase/GRα Decrease	GRβ is the dominant negative of GRα. High levels of GRβ with low levels of GRα has been implicated in glucocorticoid resistance.	[7, 102]
High FKBP51 Expression	Binding of FKBP51 to GR complex keeps GR inactive. High expression of FKBP51 can lead to glucocorticoid resistance by keeping GR inactive.	[7, 88]
Low FKBP52 Expression	FKBP52 bound to GR complex is correlated with active GR. Low expression of FKBP52 has been correlated to glucocorticoid resistance.	[7, 88]
High PP5 Activity	PP5 dephosphorylates GR at S211, which is an important site for active GR. High PP5 activity contributes to glucocorticoid resistance.	[7, 88]
MAPK signaling	MAPKs have been shown to regulated GR phosphorylation in vivo in a tissue specific manner.	[7, 85]
NFκB signaling	Sustained NFκB signaling causes an increase in inflammation and counteracts glucocorticoids anti-inflammatory properties, contributing to glucocorticoid resistance.	[7, 87, 103]

Signal transduction pathways affected by glucocorticoid resistance include the mitogen-activated protein kinases (MAPKs) and NF-κB pathways (Figure 2) [82]. Upon binding to GRα, glucocorticoids initiate a signaling cascade in which MAPK activation is suppressed through mechanisms such as upregulation of MAPK phosphatases, including DUSP1, and induction of anti-inflammatory effects [83]. Other instances of MAPK signaling, such as glucocorticoid regulation of MAPK p38, are complex and tissue-specific. In lymphoid cells, glucocorticoid-induced p38 activation leads to apoptosis [84]. In airway smooth muscle cells, active p38 maintains GRα in an inactive state [85]. Therefore, increased p38 activity may contribute to glucocorticoid resistance in certain tissues. Stimulatory signals from IL-2 on T cells enhance ERK signaling, which is crucial in the development of glucocorticoid resistance [86]. Generally, glucocorticoids suppress NF-κB activity by interacting with its subunits or binding to its DNA response elements (κBREs) [87]. When these interactions are disrupted, NF-κB activation persists, leading to the activation of inflammatory genes and thereby contributing to glucocorticoid resistance [87].

Signaling pathways involving immunophilins (also known as tetratricopeptide repeat (TPR) proteins) such as FK506-binding protein-51 (FKBP51), FKBP52, and protein phosphatase 5 (PP5) also contribute to glucocorticoid sensitivity or insensitivity. The binding of FKBP51 to GR inhibits GR activity and glucocorticoid sensitivity, and overexpression of FKBP51 has been shown to contribute to glucocorticoid resistance [88]. Conversely, reduced levels of FKBP52 are associated with glucocorticoid resistance [89] and metabolic dysfunction [90]. Other GR-interacting proteins, such as PP5, have been demonstrated to facilitate the nucleocytoplasmic shuttling of GR [88]. PP5 also diminishes GR activity through the dephosphorylation of serine 211 [91]. Phosphorylation of serine 211 is correlated with ligand-activated GR [88]. Therefore, increased PP5 levels may contribute to a glucocorticoid-resistant state [7]. Targeting TPR proteins with specific inhibitors could be beneficial for managing CKM syndrome (Table 2).

Co-chaperones modulate nuclear receptor activity by physically binding to the receptor and altering its ability to translocate into the nucleus. One example of this paradigm is the larger FKBP proteins bound to the GR heterocomplex, namely FKBP51 and FKBP52. FKBPs are a family of proteins that have peptidyl-prolyl cis-trans isomerase (PPIase) activity. PPIase activity is inhibited by immunosuppressant ligands; therefore, these proteins are referred to as immunophilins [92]. FKBP proteins are involved in immunoregulation, protein folding, and trafficking. FKBP51 and FKBP52 are two immunophilins that regulate nuclear receptor translocation [7]. FKBP51 knockout mice exhibit increased GRα-mediated lipolysis and decreased adipogenic activity via PPARγ [88]. FKBP51 has been identified as a reciprocal regulator of both GRα and PPARγ [88].

Both FKBP51 and FKBP52 bind to the GR heterocomplex and exert opposing effects on its transcriptional functions [93]. FKBP52 functions as a positive regulator of GRα, whereas FKBP51 acts as a negative regulator of its signaling. These proteins compete for binding within the GR heterocomplex [93]. Both FKBP51 and FKBP52 contain TPR domains, which interact with heat shock protein 90 (HSP90) (Figure 2). HSP90 is integral to the GR activation complex, stabilizing its active conformation. A regulatory switch occurs in which FKBP51 dissociates from the GRα-HSP90 complex and FKBP52 associates, thereby enhancing glucocorticoid affinity, promoting nuclear translocation, and augmenting GRα’s hormone signaling [93].

NR3C1 Gene Mutations Causing Glucocorticoid Resistance

Mutations in the NR3C1 gene encompass missense, nonsense, frameshift, splice-site, and deletion and insertion mutations [94, 95]. Glucocorticoid resistance may result from genetic mutations, including single-nucleotide polymorphisms (SNPs) within the NR3C1 gene. Some of these polymorphisms contribute to glucocorticoid resistance. A total of 60,309 NR3C1 gene SNPs have been documented through Ensembl. Numerous SNPs have been associated with glucocorticoid resistance. Notably, four polymorphisms—N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189 and rs6190), and 9β (rs6198)—have been extensively studied.

Since the term CKM syndrome was recently introduced by the American Heart Association (AHA) only in October 2023 [14], we focused on SNPs associated with inflammatory conditions, as inflammation is a common factor in the progression of CKM syndrome. The polymorphisms N363S (rs6195) and BclI (rs41423247) are associated with heightened sensitivity to glucocorticoids [96]. These variants are also linked to a reduced risk of rheumatoid arthritis (RA) compared to healthy controls [96], which is an inflammatory disease. Conversely, carriers of ER22/23EK (rs6189/rs6190) and 9β (rs6198) tend to have glucocorticoid resistance and a higher likelihood of RA [96]. The 9β variant is located within the GRβ mRNA, suggesting that targeting this mutation could be a promising therapeutic approach. BclI and N363S polymorphisms are associated with more severe multiple sclerosis [97]. The BclI mutation has also been associated with increased body weight and greater total body fat in women [98]. In women, the NR3C1 rs6190 polymorphism is associated with elevated cholesterol levels and more advanced atherosclerotic lesions [99]. A study on patients with the 9β polymorphism revealed a higher prevalence of the GRα TT-genotype in PBMCs from septic patients who died within 30 days, along with increased levels of pro-inflammatory cytokines IL-12, IL-23, and IFN-γ [100]. These mutations may reduce glucocorticoid binding to GRα, impair nuclear translocation, disrupt transcriptional activity, and increase GRβ expression, leading to effects such as inflammation and glucocorticoid resistance [44]. In summary, abnormalities in signaling pathways and receptor function lead to physiological changes that influence glucocorticoid sensitivity and resistance.

Translational and Therapeutic Aspects

Numerous drugs and compounds currently under research might be useful for addressing glucocorticoid resistance in CKM syndrome. Table 3 presents potential pharmacological agents aimed at improving glucocorticoid and insulin sensitivity within CKM syndrome. While other options may exist, these were highlighted based on the discussion. Steroidal and non-steroidal MR antagonists, which inhibit excessive glucocorticoid activity and MR activation, could help reduce sodium and water retention, improve fibrosis in heart failure, reverse resistant hypertension, and treat CKD [101]. The non-steroidal MR antagonist Finerenone, approved by the FDA to lower CVD risk in patients with CKD and type 2 diabetes [101], seems most appropriate for treating CKM stages 3 and 4 (Table 1). Other agents, such as TZDs, insulin sensitizers that enhance insulin sensitivity and reduce inflammation, might be effective in CKM stages 1 and 2.

Table 3.

Potential treatment options for glucocorticoid resistance and CKM syndrome.

Intervention	Summary	Ref
Dasatinib	Primary BCP-ALL cells surviving glucocorticoid treatment in vitro and in vivo have activated PI3K/mTOR signaling. Dasatinib, which is a multikinase inhibitor, effectively targeted this signaling pathway in glucocorticoid-resistant cells. Dasatinib combined with glucocorticoids resulted in increased cell death in vitro, decreased leukemic burden, and prolonged survival in vivo.	[34]
Timcodar (VX-853), SAFit1, and SAFit2	FKBP51, a TPR-containing protein, exhibits elevated expression in white adipose tissue. This overexpression is attributed to elevated glucocorticoid activity, aldosterone levels, weight gain, or metabolic dysfunction. Timcodar, SAFit1, and SAFit2 are all FKBP51-specific antagonist. Blocking FKBP51 with these drugs has demonstrated reduced lipid accumulation or reduced body weight and increased glucose sensitivity. This shows potential for improved metabolic outcomes.	[88]
Thiazolidinediones (TZDs) (Rosiglitazone and Pioglitazone)	Insulin sensitizers used to treat type 2 diabetes by activating PPARγ to improve insulin sensitivity and reduce inflammation.	[104]
Steroidal Mineralocorticoid Antagonist (Spironolactone and Eplerenone)	A class of drugs that block MR activation, reducing sodium/water retention and fibrosis in heart failure, resistant hypertension, and chronic kidney disease (CKD).	[101]
Non-Steroidal Mineralocorticoid Antagonist (Finerenone)	FDA-approved for reducing cardiovascular risks in patients with chronic kidney disease (CKD) and type 2 diabetes.	[101]
JTT-654	11βHSD1 plays a pivotal role in regulating the expression of glucocorticoid action and its overexpression in adipose tissue can lead to hypertension. JTT-654 is a novel 11βHSD1 inhibitor which improved hypertension in cortisone-treated, spontaneously hypertensive, and genetically obese, hypertensive, and diabetic (SHR/NDmcr-cp) rats.	[76]
Amiloride and Hydrochlorothiazide	Amiloride and hydrochlorothiazide are used in combination as diuretics. 11βHSD2 KO mice fed a normal salt diet develop hypertension. The phenotype of the11βHSD2 KO mice aligns with apparent mineralocorticoid excess (AME) syndrome. This is improved by administration of amiloride and hydrochlorothiazide as well as a low-salt diet.	[79]

CONCLUDING REMARKS

Glucocorticoid resistance is a central driver of CKM syndrome, linking stress, inflammation, and metabolism. It plays a key role in the development of this systemic disorder, which includes obesity, diabetes, CKD, and CVD. Excess cortisol in glucocorticoid resistance triggers MR activation and proinflammatory signaling, leading to a chronic low-grade inflammatory state that causes insulin resistance in CKM stage 1. This condition then progresses to more advanced stages involving CKD and CVD. Therefore, an MR antagonist could provide therapeutic benefits by addressing glucocorticoid resistance and improving CKM health. Potential treatments for CKM syndrome include several important ideas outlined in the Outstanding Questions section, which pose the central question of whether MR antagonists can improve CVD in later stages of CKM and whether insulin-sensitizing medications can benefit in the early stages. PPARγ agonists (TZDs) may worsen CKM health because of their side effects of cardiomyopathy and CVD, which is a criterion in the advanced CKM stages 3 and 4. Future strategies to restore glucocorticoid sensitivity could benefit those with CKM syndrome. It would be helpful to determine whether 11β-HSD1 inhibitors enhance insulin sensitivity and reduce inflammation in early stages of CKM, and whether they also offer advantages in later stages. Additionally, developing blood biomarkers to predict CKM syndrome progression is essential. Developing strategies to target glucocorticoid resistance and a better understanding of GR isoform signaling could open new avenues to improve CKM health.

Figure I.

Canonical Glucocorticoid Receptor Expression, Signaling, and the Events Leading to Glucocorticoid Resistance and Inflammation.

Outstanding Questions Box.

• Can reversing glucocorticoid resistance through the use of insulin-sensitizing medications enhance disease outcomes in CKM stages 1 or 2 of CKM syndrome?

• Would a mineralocorticoid receptor antagonist be effective in the treatment of cardiovascular disease during stages 3 and 4 of the CKM syndrome?

• Will the kinase inhibitor Dasatinib be effective in treating glucocorticoid resistance in CKM syndrome by suppressing kinases responsible for phosphorylating GRα, thereby restoring glucocorticoid activity?

• Are there biomarkers of glucocorticoid resistance available that can be utilized to predict the progression of CKM Syndrome?

• Does tissue-specific dysregulation of glucocorticoids contribute to chronic inflammation, insulin resistance, and other adverse physiological consequences associated with CKM Syndrome?

• Are there single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor that influence the prognosis of CKM Syndrome, either by exacerbating or mitigating outcomes?

Highlights.

• In glucocorticoid resistance, glucocorticoid levels and their binding to the glucocorticoid receptor are impaired, which leads to increased inflammation and the development of CKM syndrome.

• Chronic excess of glucocorticoids causes inflammation by activating the mineralocorticoid receptor and elevating glucocorticoid receptor beta levels, leading to hypertension and increased fat accumulation.

• Targeted regulation of glucocorticoid resistance in specific tissues could enhance treatment outcomes for inflammation and lipid build-up in cases of glucocorticoid resistance and CKM syndrome.

• 11β-HSD1 and 11β-HSD2 may be dysregulated in cases of glucocorticoid resistance and CKM Syndrome.

• Several potential target proteins and pathways have been identified for developing therapeutics for CKM syndrome.

Glossary

11β-hydroxysteroid dehydrogenase type 1 and 2

Enzymes that interconvert active and inactive glucocorticoids, regulating local hormone availability and influencing metabolic and inflammatory processes.

β-oxidation pathway

A metabolic process in which fatty acids are broken down in the mitochondria to produce energy in the form of ATP.

Cardiovascular-Kidney-Metabolic (CKM) syndrome

A cluster of interconnected conditions involving the heart, kidneys, and metabolism that increase the risk of cardiovascular disease and mortality.

Cardiovascular Disease (CVD)

A group of disorders affecting the heart and blood vessels, including coronary artery disease, heart failure, and stroke.

Chromatin

The complex of DNA and proteins (mainly histones) that packages genetic material within the nucleus and regulates gene expression.

Chronic Kidney Disease (CKD)

A long-term condition characterized by a gradual loss of kidney function, often linked to hypertension, diabetes, and metabolic disorders.

Coregulator proteins

Molecules that interact with nuclear receptors like the glucocorticoid receptor to either enhance (coactivators) or suppress (corepressors) gene transcription.

Glucocorticoid excess

A condition of sustained high glucocorticoid levels, which can lead to metabolic disturbances, immune suppression, and increased cardiovascular risk.

Glucocorticoid resistance

A state in which cells exhibit reduced sensitivity to glucocorticoids, leading to impaired anti-inflammatory and metabolic hormone responses.

Glucose Tolerance Test (GTT)

A diagnostic test that measures the body’s ability to metabolize glucose, commonly used to assess insulin sensitivity and diagnose diabetes.

Hepatocarcinoma (HCC)

A primary malignant tumor of the liver, often arising from chronic liver disease or cirrhosis, including diseases such as MASH and MASLD.

Hypothalamic–Pituitary–Adrenal (HPA) axis

A neuroendocrine system that regulates stress responses, metabolism, and immune function through interactions among the hypothalamus, pituitary gland, and adrenal cortex.

Insulin Clearance

The process by which insulin is removed from circulation, mainly by the liver and kidneys, influencing insulin sensitivity and glucose metabolism.

Insulin Resistance

A metabolic condition where cells respond poorly to insulin, resulting in impaired glucose uptake, hyperinsulinemia, and increased risk of type 2 diabetes.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

A liver disorder characterized by excess fat accumulation in the liver associated with metabolic dysfunction, formerly known as nonalcoholic fatty liver disease (NAFLD).

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

A progressive form of MASLD marked by liver inflammation, hepatocyte injury, and fibrosis, which can lead to cirrhosis or hepatocellular carcinoma.

Oxidative stress

A state in which the production of reactive oxygen species (ROS) exceeds the body’s antioxidant defenses, leading to cellular damage and contributing to metabolic and inflammatory diseases.

Peptidyl-prolyl cis-trans isomerase (PPIase)

An enzyme that catalyzes the interconversion between cis and trans isomers of peptide bonds at proline residues, aiding protein folding.

Single-Nucleotide Polymorphisms (SNPs)

Genetic variations involving a single nucleotide change in DNA, which can influence disease susceptibility and drug response.

Tetratricopeptide Repeat (TPR) proteins

A family of proteins containing structural motifs that mediate protein-protein interactions, often involved in chaperone and signaling functions.

Type 2 Diabetes

A metabolic disorder characterized by insulin resistance and relative insulin deficiency, leading to hyperglycemia and increased risk of cardiovascular and kidney disease.