Mineralocorticoid receptor antagonists promote renal immunosenescence

Abstract

Chronic kidney disease (CKD) is often associated with chronic inflammation, influenced by the activation of mineralocorticoid receptors (MR). This review focuses on changes in immune cells and explores the important role that MR antagonists (MRAs), especially the new nonsteroidal MRA, finerenone, play in alleviating renal and cardiac injury by affecting the transformation of stimulated immune cells. We found that MR can promote the transformation of macrophages to M1 pro-inflammatory phenotype through IL-14 receptor and mitogen-activated protein kinase (MAPK)–JNK. MR also activates helper T cells and reduces the generation of regulatory T cells by promoting the interaction between nuclear factor and activator protein-1, increasing the secretion of IL-2 and IL-18, increasing the expression of CD38 and CD69, especially the IL-17/IL-23 axis. The above immune system changes jointly mediate inflammation leading to kidney damage and fibrosis. In addition, we propose that the NLRP3 inflammasome is associated with macrophage imbalance. Preclinical studies indicate that finerenone effectively reduces inflammation and prevents structural kidney damage without significant systemic blood pressure changes. These data will provide some ideas for further research in the field of immune mechanisms in future, and drug research targeting specific targets and channels may also become a new type of diagnostic and treatment measure.

Background

Patients with chronic kidney disease exhibit a coexisting inflammatory state and immune dysregulation. It has been demonstrated that kidney disease may result in the local enhancement of renal innate immunity, while simultaneously leading to the systemic activation and dysfunction of the innate immune system [1]. The process of aging is associated with alterations in the immune system, a phenomenon known as immunosenescence [2]. Aging reduces glomerular filtration rate (GFR) and impairs kidney function. In chronic kidney disease (CKD), aging contributes to structural damage and immune dysfunction. Combined with genetic/environmental factors that disrupt metabolism and increase oxidative stress, these age-related changes raise CKD risk in older adults [3].

Aldosterone binds to intracytoplasmic receptors, forming a hormone-receptor complex, which then enters the nucleus through the nuclear membrane. There, it synthesizes aldosterone-induced protein through various mechanisms. Inflammation has been shown to play an important role in the pathophysiology of chronic kidney disease [4]. Aldosterone can induce inflammation through pathological activation of mineralocorticoid receptors (MRs) in the kidney and heart [5].The mineralocorticoid receptor, a member of the nuclear receptor family, binds mineralocorticoids and glucocorticoids with high affinity [6], and is the major receptor for the hormone aldosterone. Previous studies have found that mineralocorticoid receptor activation has specific effects on various cell types – cardiomyocytes, endothelial cells, vascular smooth muscle cells, adipocytes, and inflammatory cells [7, 8]. Inflammation or immune system activation plays an important role in the pathophysiology of aldosterone-promoted vascular injury [9]. The renal protective effect of aldosterone blockade has been attributed to its antifibrotic activity, and the presence of inflammation is crucial in the pathogenesis of renal fibrosis [10]. The immune response ages with age and is characterized by increased susceptibility and a sustained systemic inflammatory response [3]. There is substantial evidence to suggest that MR antagonists possess an aldosterone-independent mechanism of action [6].This review examines the principal mechanisms of action of mineralocorticoid receptor antagonists (MRAs), including novel nonsteroidal MRAs, on renal immune cell regulation, and presents a synthesis of the clinical effects of MRAs.

Expression and function of MR in renal immune cells

Inflammatory cells (dendritic cells, macrophages, and T cells) are all involved in aldosterone-modulated mineralocorticoid receptor-induced inflammatory responses in both renal and cardiac tissues. A substantial body of evidence from numerous studies indicates that the immune system plays a pivotal role in aldosterone-mediated fibrosis and tissue damage. Furthermore, these studies demonstrate that the immune system serves as a crucial mediator of MR.

Expression and function of MR in macrophages

Macrophages play a role in inflammatory responses and the maintenance of tissue repair and remodeling. There is compelling evidence that the degree of infiltration of pro-inflammatory macrophages is closely correlated with the severity of renal injury in both acute kidney injury and chronic kidney disease models. IL-4 receptor is a key signaling pathway for the induction of M2 macrophages. MR activation interferes with IL-4 signaling and promotes the polarization of macrophages toward M2 pro-inflammatory phenotype [11]. The stimulation of steroid hormones in mouse macrophages has been observed to give rise to pro-inflammatory effects, manifested as a transformation into the M1 phenotype [12]. The activation of nuclear hormone receptors (PPARγ and PPARδ) directly drives macrophages toward a selectively activated state, namely, an M2 phenotype [13, 14].

MR deficiency has been demonstrated to suppresses migration and proliferation of macrophages and suppresses macrophage inflammatory responses via the SGK1-AP1/NF-κB pathway [15]. It seems that mineralocorticoid receptor signaling may stimulate the mitogen-activated protein kinase (MAPK)- cJun N-terminal kinases (JNK) pathway independently of other pathways[16]. The phosphorylation of JNK was markedly elevated in bone marrow-derived macrophages following exposure to LPS, a prototypical type 1 pro-inflammatory mediator.

In the presence of aldosterone, macrophages undergo rapid proliferation and infiltration. Infiltrating macrophages have the capacity to release a number of active products commonly associated with inflammatory responses, including lysosomal enzymes, nitric oxide, reactive oxygen intermediates, and TGF-β. These have been identified as key factors in the development of glomerular and tubular damage. In the event of damage to the glomeruli or renal tubules, a series of inflammatory factors and chemokines are produced, including chemokine-1 and RANTES (regulated by normal T cell expression and secretion). These factors can attract macrophages to proliferate and infiltrate the kidneys, migrate to the site of kidney damage, and subsequently release a substantial number of pro-inflammatory and oxidative stress products, thereby producing a phenomenon analogous to a cytokine storm.

NLRP3 inflammasome is a protein complex composed of NLRP3 protein, ASC, and caspase-1 [17]. It has been demonstrated that this process can facilitate the processing of caspase-1-mediated pro-inflammatory cytokines, namely, IL-1β and IL-18. In the kidneys of rats treated with aldosterone, there was an increase in the infiltration of macrophages and T lymphocytes, which were capable of producing a substantial quantity of inflammatory mediators, including MCP-1, TNF-α, inflammasome activation markers IL-1β, caspase-1, and NLRP3. Additionally, the formation of reactive oxygen species, as well as the IGF-1 signaling pathway, was observed [12, 18]. Aldosterone is an important activator of NLRP3 inflammasome, and its activation mechanism involves NF-κB signaling pathway. And the activation of the NLRP3 inflammasome is associated with an imbalance in the M1/M2 macrophage populations. Wu et al. demonstrated that the VEGFR3-AMPK-dependent autophagy pathway in macrophages can inhibit the activation of NLRP3 inflammasome in salt-sensitive hypertensive mice and alleviate NLRP3 inflammasome-associated CASP-1 activation in macrophages, thereby preventing renal inflammation [19].

Expression and function of MR in T cell

It is evident that MR in T cell plays a critical role in the development of renal fibrosis [20]. Aldosterone further activates T cells through dendritic cell-dependent activation and secretion. Aldosterone can promote the interaction with the nuclear factor of activated T cells (NFAT-1) and activator protein-1 (AP1) by activating MR [21], thereby promoting the increase and infiltration of T cells and promoting the transformation of CD4 + T cells into pro-inflammatory T helper cells phenotype, as well as reducing T regulatory (Treg) cell number, which controls IFN-γ in T cells and regulates target organ damage [21].

The induction of aldosterone results in the simultaneous upregulation of CD69 and the secretion of IL-2 and IFN-γ, which in turn promotes increased activation of CD8 + T cells [22]. Thales et al. demonstrated that the blockade of the MR was capable of counteracting the thymic dysfunction induced by ethanol consumption. This was achieved by preventing the activation of nicotinamide adenine dinucleotide phosphate oxidase and the subsequent production of superoxide, which resulted in alterations to T cell maturation [23, 24]. MR plays a role in regulating peripheral T cells, promoting tissue infiltration and facilitating the activation of double-positive CD4⁺ and single-positive CD8⁺ cells [25]. In studies of rats treated with DOCA-salt, DOCA was found to activate helper T cells and reduce the production of regulatory T cells [26].

MR activation promotes T cell proliferation and differentiation, leading to the release of IL-17. The study revealed that IL-17 in mice is contingent upon IL-6 and TGF-β, which are produced by dendritic cells in response to aldosterone via the p38 and JNK MAPK pathways, polarizing CD4 T cells to a Th17 phenotype. Th17 cells require IL-23 for expansion and survival. IL-23 is released by activated dendritic cells and macrophages [27]. And γδ T cells, which, in addition to inducing the secretion of substantial quantities of IL-17, are also capable of secreting cytokines such as interferon γ, IL-6, and perforin [28]. In a DOCA-salt hypertensive mouse model, finerenone prevented cardiorenal injury by reducing renal accumulation of IL-17-producing RORγ⁺ γδ T cells, thereby lowering urinary albumin-to-creatinine ratio (UACR) and demonstrating renoprotection [29].

In MRKO mice, Ang II-induced glomerular hypertrophy was prevented and proteinuria levels were significantly improved. CD8 + cells exert a more pronounced influence on Ang II-induced hypertension and organ damage than CD4 + , and activated CD8 T cells secrete a greater quantity of IFNγ than CD4 T cells [30, 31]. (The above mechanisms are summarized Fig. 1.)

Fig. 1.

Aldosterone-mediated pro-inflammatory effects in macrophages and T cells. (By Fig-draw)

Under aldosterone stimulation, mineralocorticoid receptors in macrophages activate signal transduction of the MAPK-JUN pathway, promoting the transformation of macrophages to the M1 pro-inflammatory type. In T cells, MR activation promotes the action of nuclear factor of T cells (NFAT) and AP1, thereby stimulating the expression of helper T cells 1 (Th1) and helper T cells 17 (Th1), while reducing the number of regulatory T cells (Treg). In addition, it can promote the activation of CD8 + T cells. These processes are regulated by NGAL and IL-23 factors released by dendritic cells. The above multiple pathways work together to produce inflammatory mediators and cause tissue damage.

Renal insufficiency and hypertension exert a mutual influence upon one another [32]. Overexpression of the MR gene in T cells resulted in an elevation of blood pressure in mice treated with Ang II. Furthermore, the treatment of DOCA-salt rats with anti-IL-17 led to a notable reduction in arterial hypertension and the expression of profibrotic and pro-inflammatory mediators in the heart and kidneys, in addition to a reduction in collagen deposition [22, 26]

Serine/threonine protein inhibitor 1 (SKG1) is expressed in both T cells and dendritic cells [33]. SKG1 was shown to be a key player in salt-stimulated and Ang II-stimulated hypertension, as well as in the development of end-stage hypertensive damage [34, 35]. SGK1 plays a regulatory role in sodium transport in renal epithelial cells, upregulating the sodium-chloride cotransporter (NCC) and the sodium epithelial channel (ENaC) [36]. And SGK1 has the capacity to directly activate T cells, independent of the involvement of dendritic cells. The specific deletion of SKG1 in T cells has been demonstrated to alleviate salt-induced renal and vascular damage [37]. In comparison to the control mice, the absence of SGK1 in T cells was observed to result in the absence of any accumulation of memory cells or inflammatory cytokines, such as IFN-γ, in the kidneys [38].

Neutrophil gelatinase-associated lipocalin

Neutrophil gelatinase-associated lipocalin (NGAL) has been shown to be a specific target for MR. There is a positive correlation between NGAL and mineralocorticoid receptor expression in immune cells, particularly in dendritic cells and macrophages [39]. The production of NGAL by immune cells is of great importance in the context of aldosterone-induced vascular fibrosis. And it has been demonstrated that NGAL is a necessary factor in aldosterone-induced inflammation in dendritic cells. In addition, Benjamin et al. demonstrated that in mice overexposed to mineralocorticoids, NGAL produced by macrophages plays a key role in renal fibrosis through the CCL5/IL-4 pathway [40].

MR activation leads to increased expression of inflammatory factors

Oxidative stress has been demonstrated to promote the production of inflammatory factors and the activation of inflammatory cells. This is achieved by forming reactive oxygen species, which have the capacity to activate MR [41]. In proximal tubular cells, Ang II induces the expression of nuclear factor kappa B (NF-κB) [42], which in turn leads to the production of IL-6, TNF-α, and IFN-γ. These effects may be mediated by increased levels of peroxisome proliferator-activated receptor γ (PPAR-γ) protein and phosphorylated Smad protein, a reduction in the expression of cardiotrophin (CT-1), and an increase in Toll-like receptor 4 (TLR4) signaling [43–46]. The aforementioned inflammatory factors incite the migration of inflammatory cells, predominantly T cells, into the renal interstitium, blood vessels, and glomeruli. This results in an excessive accumulation of collagen and extracellular matrix, which ultimately culminates in renal tissue fibrosis. Spironolactone has a direct inhibitory effect on T cell activation based on the inhibition of NF-κB activity [22]. In the study conducted by Sandor et al. [47], low-dose MRA has also been demonstrated to directly reduce the effects of renal profibrotic factors (TGFβ1, PDGF, CTGF/CCN2, etc.) and the production of extracellular matrix (ECM) by fibroblasts. The substantial accumulation of extracellular matrix (ECM) represents a significant pathological foundation for the development of glomerulosclerosis [48]. Studies show pronounced immunosenescence in CKD patients, characterized by T/B cell dysregulation/accumulation and elevated pro-inflammatory cytokines (e.g., IL-17/IL-23) [3].

Comparison of steroidal and nonsteroidal MRA antagonists

Differences in pharmacological mechanisms

Spironolactone, a classic mineralocorticoid receptor antagonist developed 50 years ago for hypertension, remains in use but causes nonselective effects (e.g., the male breast gland, hyperkalemia, and renal impairment). The more selective MR antagonist eplerenone was later developed, but shows reduced efficacy and a short 3-h half-life [49, 50]. Both drugs carry significant hyperkalemia risks.

A number of drugs are currently in development (CS-3150, PF-03882845, DSR-71167), with finerenone representing the most advanced. Its chemical structure was derived from that of dihydropyridine channel blockers, without any activity against L-type calcium channels [51]. Finerenone has a considerably shorter half-life than steroidal MRAs and lacks active metabolites [52]. Additionally, it exhibits greater MR selectivity than spironolactone and a higher receptor binding affinity than eplerenone, and demonstrates a reduction in serum potassium elevation, a lower incidence of hyperkalemia, and a lower incidence of renal impairment in patients with heart failure and chronic kidney disease [53, 54].

Preclinical research

MR antagonists (MRAs) exhibit significant anti-inflammatory effects by reducing immune cell infiltration. In myeloid-specific MR knockout (MyMRKO) mice, eplerenone treatment markedly decreased neutrophil, CD4 + /CD8 + T cell, and macrophage accumulation, along with inflammatory mediators (TNF-α, matrix metalloproteinase12, inducible nitric oxide synthase) [55]. TNF-α, a key pro-inflammatory cytokine in hypertensive end-organ damage, is suppressed by MRAs. Eplerenone also downregulates renal leukocyte adhesion molecules and pro-inflammatory genes, particularly inhibiting macrophage recruitment and M2 phenotype polarization [56–58]. Mechanistically, MRAs block MR-PPARγ crosstalk in macrophages, promoting an M2 anti-inflammatory state [58]. In vitro studies further confirm MR’s direct modulation of CD4 + T cell activation.

Comparison with the steroidal MR antagonist, eplerenone, finerenone is more effective at reducing the production and release of pro-inflammatory cytokines and can effectively reduce macrophage infiltration and activation, in preclinical rat disease models, and significantly reduces immune cell activity and infiltration in cardiorenal tissue [53]. Kidney injury can arouse the secretion of numerous inflammatory cells, which in turn secrete a variety of growth factors, including TGF-β, EGF, and FGF-2. These growth factors stimulate epithelial–mesenchymal transition (EMT). During the process of fibrosis, some subpopulations of these fibroblasts express αSMA and synthesize a substantial quantity of extracellular matrix proteins, leading to fibrosis of renal tissue, particularly affecting renal tubular epithelial cells [59]. In diabetic mice fed a high-salt diet, the novel nonsteroidal MRA esaxerenone demonstrated efficacy in inhibiting renal inflammation and renal fibrosis by selectively blocking MR, as evidenced by its superior efficacy compared to spironolactone [60].

Finerenone protects against functional and structural renal and cardiac damage in rats at doses that do not reduce systemic blood pressure [53]. Kolkhof et al. observed that [C]-labeled finerenone was distributed uniformly in the hearts and kidneys of rats using quantitative whole-body autoradiography. In comparison to eplerenone, it proved to be more efficacious in the reduction of myocardial hypertrophy, plasma pro-brain natriuretic peptide hormone levels, and proteinuria.

The new nonsteroidal MRA has good benefits in the prevention of acute kidney injury following ischemia–reperfusion and its subsequent transformation to chronicity. Lattenist et al. demonstrated that finerenone can prevent the increase of oxidative stress and ET-B sulfenic acid modification in the kidney after ischemia [61]. The MR antagonism of finerenone can reduce the mRNA levels of lipoprotein-related tubular injury markers, including kidney injury molecule-1 and neutrophil gelatinase. Moreover, this mechanism has been shown to prevent the development of acute kidney injury in models of ischemia–reperfusion (IR).

Conclusion and future outlook

Notably, the nonsteroidal MRA finerenone effectively reduces inflammation, proteinuria, and renal damage without significant hyperkalemia risk. Studies demonstrate its superior cardiorenal benefits and safety compared to older MRAs. By modulating T cell function, inhibiting pro-inflammatory cytokines, and reducing oxidative stress, finerenone shows promising cardiorenal protective effects.

The data will facilitate the identification of new biomarkers and therapeutic targets. Furthermore, the reduction of inflammatory factor production, the specific pathway knockout, and the inhibition of immune cell subtype transformation may represent a novel direction for the development of treatments.

This review highlights the key roles of both steroidal and nonsteroidal MRAs in immune pathways during renal injury progression. MRAs provide significant protection by counteracting harmful mineralocorticoid effects on kidneys and heart. They reduce renal inflammation, decrease pro-inflammatory factors, and slow tissue fibrosis. Additionally, MRAs improve T cell function, modulate immune responses, and limit immune cell infiltration, as demonstrated in diabetic and high-salt diet kidney injury models.

There are notable distinctions in the molecular and pharmacological characteristics between steroidal and nonsteroidal MRAs. In particular, the new nonsteroidal MRA finerenone has been demonstrated to effectively reduce the inflammatory response, reduce proteinuria and renal structural damage without significantly increasing the risk of hyperkalemia. The results of these studies illustrate that the drug has notable benefits for the kidneys and heart, while also demonstrating a favorable safety profile in comparison to older MRA medications. MRA shows promise in improving cardiorenal function by modulating T cell function, inhibiting the release of pro-inflammatory cytokines, and alleviating oxidative stress.

Emerging research directions in CKD treatment should focus on elucidating the blood pressure-independent cardiorenal protective mechanisms of MRAs, as demonstrated in FIDELIO-DKD, including their potential effects on neutrophils and NK cells observed in angiotensin II-induced hypertension models [62, 63]. Therapeutic strategies could target multiple inflammatory pathways (IL-4R, MAPK-JNK, IL-17/23 axis, and NF-κB downstream factors) to reduce oxidative stress and macrophage infiltration, while novel approaches combining MRAs with IL-17 inhibitors or senolytics may simultaneously address immunosenescence and cellular senescence. Additionally, modulation of immune cell subtypes and selective channel inhibition represent promising treatment avenues, though further studies are needed to validate these mechanisms and develop optimized therapeutic regimens for CKD management.

Abbreviations

CKD

Chronic kidney disease

MR

Mineralocorticoid receptors

GFR

Glomerular filtration rate

MRAs

Mineralocorticoid receptor antagonists

MAPK

Mitogen-activated protein kinase

VEGFR3

Vascular endothelial growth factor receptor 3

TFEB

Transcription factor EB

PRKN

Parkin RBR E3 ubiquitin protein ligase

NFAT-1

Nuclear factor of activated T cells 1

AP1

Activator protein-1

Treg

T regulatory cell

SKG1

Serine/threonine protein inhibitor 1

NCC

Sodium-chloride cotransporter

ENaC

Sodium epithelial channel

NGAL

Neutrophil gelatinase-associated lipocalin

PPAR-γ

Peroxisome proliferator-activated receptor γ

NF-κB

Nuclear factor kappa B; CT-1, cardiotrophin-1

TLR4

Toll-like receptor 4; ECM, extracellular matrix

TMRKO

T cell MR knockout

EMT

Epithelial–mesenchymal transition

T2DM

Type 2 diabetes mellitus

UACR

Urinary albumin-to-creatinine ratio

NK cell

Natural killer cell

Author contributions

Yi Yang planned and supervised the manuscript. Qiaorui Wang wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.