Am J Transl Res 2024;16(8):4246-4255

www.ajtr.org /ISSN:1943-8141/AJTR0156540

Review Article
Aldosterone’s impact on kidney health: exploring
the benefits of mineralocorticoid receptor
antagonists for renal protection
Zige Liu1,2, Boji Xie2, Shuting Pang2, Yuli Xie1,3, Mujia Jili1,3, Zengnan Mo1, Wei Li2, Rirong Yang1,3
1
Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine,
Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University,
Nanning 530021, Guangxi, China; 2Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical
University, Nanning 530021, Guangxi, China; 3Department of Immunology, School of Basic Medical Sciences,
Guangxi Medical University, Nanning 530021, Guangxi, China
Received March 13, 2024; Accepted July 16, 2024; Epub August 15, 2024; Published August 30, 2024

Abstract: Aldosterone, a hormone synthesized by the adrenal cortex, plays a crucial role in regulating sodium and
potassium levels in the kidneys through interaction with the mineralocorticoid receptor (MR) in the distal tubules
and collecting ducts. While aldosterone aids in maintaining fluid balance by promoting sodium reabsorption and
potassium secretion, elevated levels can lead to inflammation, oxidative stress, and organ damage. Experimental
evidence highlights aldosterone’s involvement in renal inflammation, collagen deposition, and fibrosis, often ex-
acerbating the effects of therapies like angiotensin-converting enzyme inhibitors (ACEIs) by increasing proteinuria
and vascular damage. Conversely, mineralocorticoid receptor antagonists (MRAs) show promise in mitigating these
harmful effects. This review integrates current knowledge on aldosterone and MRAs, emphasizing their roles in
renal health from both clinical and experimental perspectives. Additionally, the novel drug finerenone has shown
favorable renal and cardiovascular outcomes in patients with diabetes and chronic kidney disease (CKD), warrant-
ing exploration of its potential use in other disease populations in future research.

Keywords: Aldosterone, chronic kidney disease, mineralocorticoid receptor antagonists, kidney injury, renin-angio-
tensin system

Introduction tensin system (RAS) can contribute to intra-glo-

merular and systemic hypertension, leading to he-
Kidney disease is a prevalent and critical global modynamically induced renal injury [3]. Fur-
health concern impacting millions of individu- thermore, Ang II, the principal mediator of RAS,
als worldwide [1]. Excessive production of aldo- can directly and indirectly promote the prolifer-
sterone, a key contributor to kidney disease, ation of mesangial cells and renal tubular cells,
can result in hypertension, electrolyte imbal- potentially resulting in stromal production and
ances, and renal fibrosis. Despite extensive tubulointerstitial fibrosis. Many studies have
research efforts in recent years, a satisfactory highlighted the beneficial impact of ACEIs or
method for managing this condition has yet to ARBs in mitigating RAS-related effects, improv-
be developed. Hypertension and proteinuria ing proteinuria, and slowing CKD progression
are recognized as primary drivers of CKD pro- [4-6].
gression, underscoring the essential role of
effective antihypertensive therapy in treatment Recent research insights suggest that aldos-
[2]. Notably, certain antihypertensive medica- terone, whether produced systemically or local-
tions, such as ACEIs and angiotensin II (Ang II) ly, plays a significant role in kidney disease,
receptor blockers (ARBs), have demonstrated alongside the adverse effects of Ang II [7].
protective effects. Experimental evidence has Hyperactivation of the MR can induce endothe-
elucidated that activation of the renin-angio- lial dysfunction, fibrinolytic disorders, oxidative

https://doi.org/10.62347/NRGG6465
 The renal benefits of mineralocorticoid receptor antagonists

Figure 1. Role of aldosterone in kidney damage and clinical benefits of aldosterone blockade by mineralocorticoid
receptor antagonists.

stress, and cardiovascular and renal fibrosis, by granular cells in the glomerular parietal
culminating in organ dysfunction, damage, and apparatus and is influenced by factors such as
failure. However, the utilization of MRAs can reduced renal blood flow, renal hemorrhage,
offer cardiorenal protection by inhibiting inflam- dehydration, and salt intake. Subsequently,
mation and fibrosis triggered by MR activation. Ang II binds to the angiotensin II receptor
This advancement has opened avenues for type 1 (AT1R), enhancing the transcriptional
employing MRAs in CKD treatment. Several activity of the aldosterone synthase gene, lead-
clinical trials have underscored the impact of ing to aldosterone production and release.
MRAs on kidney disease progression and de- Potassium also plays a role in regulating aldo-
velopment. Notably, recent studies on a novel sterone independent of the RAS by affecting
MRA named finerenone have been published calcium channels. Activation of calcium-regu-
[8, 9]. Finerenone, a novel nonsteroidal MRA lated protein kinases by calcium influx pro-
with high selectivity and potent MR blockade, motes the expression of transcription factors
exhibits definitive cardiorenal protective ef- and calcium-binding proteins, further stimulat-
fects, further underscoring the therapeutic ing aldosterone synthase gene expression and
potential of this drug class. This review delves aldosterone secretion. Notably, aldosterone is
into the influence of aldosterone on kidney dis- not only produced in the adrenal gland but also
ease progression and explores the potential in extrarenal tissues such as the heart, blood
role of MRAs in managing kidney disease vessels, and brain [11, 12]. The local RAS in
(Figure 1). vascular smooth muscle cells generates Ang II,
which in turn stimulates aldosterone produc-
Synthesis and secretion of aldosterone tion and secretion. Adipocytes can also synthe-
size aldosterone through calcium-regulated
Aldosterone, a steroid hormone, was initially neuro-phosphatase signaling pathways, influ-
identified in the 1950s and is produced and encing cell differentiation and vascular func-
released by the adrenal cortex [10]. It plays a tion in an autocrine and paracrine manner [13].
pivotal role in maintaining fluid and electrolyte
balance in the body. The synthesis and secre- Recent research has dramatically transformed
tion of aldosterone are primarily governed by our understanding of aldosterone secretion in
RAS, as well as the levels of sodium and potas- the past few decades. It is now recognized that
sium ions. Renin, an enzyme, is synthesized aldosterone release is not solely driven by

4247 Am J Transl Res 2024;16(8):4246-4255

 The renal benefits of mineralocorticoid receptor antagonists

angiotensin, as various other factors can stimu- stimulation, or delayed, promoting the synthe-
late its production. Increased sympathetic ner- sis of new proton pumps, ion channels, and
vous system activity can trigger aldosterone transporters, thereby enhancing their abun-
secretion, potentially contributing to elevated dance on the plasma membrane [18]. Epithelial
aldosterone levels during stress [14]. Addition- sodium channels (ENaC) act as the final effec-
ally, factors such as low plasma sodium levels, tors of renal aldosterone activation and its
high potassium levels, hypovolemia, hypoglyce- receptor system, facilitating sodium-water re-
mia, and atrial natriuretic peptide can also absorption and regulating body fluid volume
stimulate aldosterone synthesis [15]. Inflamma- and blood pressure. The circulating glucocorti-
tion and certain medications like nonsteroidal coid-regulated kinase 1 (SGK1) serves as a
anti-inflammatory drugs may impact aldoste- crucial downstream molecule, a serine-threo-
rone levels as well [16]. These discoveries have nine kinase activated approximately thirty min-
reshaped our comprehension of aldosterone, utes post-aldosterone stimulation, correlating
underscoring the intricate interplay of multiple with an elevation in cell surface ENaC density
factors in its regulation. This complex regulato- [19]. SGK1 phosphorylates and inhibits the
ry network shifts the perception of aldosterone ubiquitin ligase Nedd4-2, preventing ENaC
secretion from being solely controlled by the degradation. Furthermore, aldosterone stimu-
RAS to being comprehensively influenced by lation upregulates the expression of pro-fibrotic
various internal and external stimuli. Further- genes like connective tissue growth factor in
more, aldosterone serves not only as a primary cardiomyocytes, indicating the influence of
ligand for the MR but also plays a crucial role aldosterone and its receptors on extrarenal tis-
in regulating sodium reabsorption to maintain sues [20]. Additionally, MR in cardiomyocytes
fluid balance. Its influence on blood pressure triggers the atrial natriuretic peptide pathway
regulation extends beyond fluid balance to by interacting with p300 and GATA4, fostering
involve vascular and central nervous system myocardial hypertrophy [17].
modulation. Moreover, aldosterone is intricate-
ly linked to a spectrum of disease-related Aldosterone possesses the capability to acti-
pathophysiological processes, beyond its role vate both genomic and non-genomic pathways,
in fluid and electrolyte regulation. leading to target organ injury (Table S1). The
non-genomic effects of aldosterone can occur
Pathways of action of aldosterone: genomic through MR binding or independently of MR via
and non-genomic crosstalk mechanisms. Notably, aldosterone
triggers a rapid and transient elevation in intra-
Historically, the effects of aldosterone were
cellular calcium levels in renal epithelial cells,
predominantly attributed to genomic pathways,
dependent on c-Src tyrosine kinase activation
where it binds to the MR to modulate gene
and transactivation of the epidermal growth
expression. The carboxy-terminal structural do-
factor receptor (EGFR) [21]. This EGFR signaling
main of MR, CT-LBD, and its specific interac-
activation subsequently impacts other path-
tion with heat shock proteins (HSPs) are pivo-
tal for its functionality [17]. In its inactive state, ways such as mitogen-activated protein kinas-
MR associates with HSP70, HSP90, and vari- es (ERK), protein kinase C (PKC), and phospha-
ous immunoaffinity proteins. Upon aldosterone tidylinositol-3 kinase (PI3K), with c-Src play-
binding, these molecules dissociate from CT- ing a pivotal role in this cascade. In vascular
LBD, activating MR and facilitating its translo- smooth muscle cells, aldosterone-induced c-
cation to the nucleus. Within the nucleus, MR Src activation leads to p38 mitogen-activated
binds to hormone response elements in the protein (MAP) and nicotinamide adenine dinu-
promoter region of target genes, leading to cleotide phosphate oxidase (NOX) 2 and NOX4
either gene activation or repression, contin- activation, culminating in collagen synthesis
gent upon the recruitment of co-activators or and reactive oxygen species production [22].
repressors in the gene transcription initiation Inhibition of AT1R can impede ERK activation,
complex. suggesting potential crosstalk between aldo-
sterone and Ang II pathways [23]. Moreover,
Aldosterone’s modulation of gene expression studies have indicated that the MR/AT1R sys-
occurs promptly, within hours of aldosterone tem activation is associated with both genomic

4248 Am J Transl Res 2024;16(8):4246-4255

 The renal benefits of mineralocorticoid receptor antagonists

and non-genomic effects linked to aldosterone aldosterone antagonist, spironolactone, miti-

stimulation [24]. Additionally, aldosterone pr- gated the rise in blood pressure and improved
ompts nuclear translocation of the G protein- left ventricular hypertrophy. These findings led
coupled receptor via the MR/AT1R system, with to the hypothesis that aldosterone is associat-
G protein-coupled receptor kinase 5 being a ed with inflammation in the heart and that its
key player in aldosterone-mediated genomic effects are primarily mediated through MR
effects leading to cellular hypertrophy. While binding. Subsequently, numerous studies have
some evidence suggests that aldosterone can demonstrated that aldosterone not only con-
activate the estrogen receptor in myocytes and tributes to the ultimate manifestation of fibro-
non-myocytes, further research is warranted to sis but also stimulates the production of inflam-
comprehensively elucidate its potential impact matory factors. Aldosterone has been shown to
on cardiac and vascular smooth muscle cells play a role in the development of inflammation
[25]. and fibrosis in the cardiovascular system and
cardiac damage [28]. The genomic pathway
It is evident that the effects of aldosterone regulates gene expression, affecting gene tran-
can manifest through both genomic and non- scription and protein synthesis within cells,
genomic pathways. While aldosterone-MR bind- thereby influencing cell function and organ
ing regulates fluid and electrolyte balance, its physiological activities. Infusion of aldosterone
non-genomic pathways play a critical role in in a rat model upregulated the expression of
mediating target organ damage through swift intercellular adhesion molecule 1 (ICAM-1) and
and direct effects. vascular cell adhesion molecule 1 (VCAM-1), as
Pathways of aldosterone-induced kidney dam- well as inflammatory markers such as cyclooxy-
age: inflammatory and fibrosis genase 2 (COX-2), monocyte chemotactic pro-
tein 1 (MCP-1), and osteopontin (OPN) prior to
In the early 2000s, animal studies indicated inflammatory cell infiltration [29, 30]. Patho-
that targeted blockade of aldosterone mitigat- logical examination of cardiac tissue revealed
ed glomerulosclerosis and reduced urinary pro- signs of coronary artery inflammation, local
tein levels in spontaneously hypertensive rats. ischemia, and necrosis.
Administration of ACEIs and ARBs also sup-
As investigations progressed, the connection
pressed proteinuria and glomerulosclerosis,
between aldosterone and renal inflammatory
but co-infusion of aldosterone reinstated the-
se indications of damage [26]. These results and fibrotic responses became increasingly evi-
strongly suggest the involvement of aldoste- dent. Terada et al. [31] reported that in mouse
rone in kidney damage. Subsequent research kidneys, aldosterone contributed to renal tract
has increasingly demonstrated a close rela- fibrosis and inflammation by stimulating the
tionship between aldosterone, MR, and the transcription of ICAM-1 and CTGF through the
advancement and onset of kidney damage, activation of SGK-1 and NF-κB. Furthermore,
which may occur through the stimulation of an MRAs notably alleviated glomerular injury. Hao
inflammatory response and fibrosis (Table S2). et al. [32] also revealed that aldosterone pro-
moted renal inflammatory responses by upreg-
During the development of the inflammatory ulating NF-κB expression. In rats injected with
response, various causes first induce the pro- aldosterone, the expression of pro-inflammato-
duction of pro-inflammatory factors, chemotax- ry factors was elevated in the kidneys, and MR
is, recruitment of immune cells, and promotion knockdown mitigated this effect. Macrophages
of local tissue damage; then active inflamma- were found to play a key role in mediating MR
tion and further infiltration of inflammatory activation-induced injury. Another study discov-
cells occur, which, if left unchecked, lead to ered increased levels of IL-6 and tumor necro-
remodeling, extracellular matrix production, sis factor alpha expression in perirenal tissues
collagen deposition, and eventually fibrosis. of patients with aldosteronism compared with
Tissue/organ remodeling and fibrosis represent those with essential hypertension, further sup-
the ultimate manifestation of the inflammatory porting the role of aldosterone in the renal
response. In the 1990s, Brilla et al. [27] report- inflammatory response [14]. In addition, renal
ed that aldosterone injection induced intersti- podocytes were found to activate NLRP3
tial and perivascular fibrosis in rats, while an inflammatory vesicles in response to aldoste-

4249 Am J Transl Res 2024;16(8):4246-4255

 The renal benefits of mineralocorticoid receptor antagonists

rone, thereby promoting the development of opment in the Framingham Offspring Cohort.
proteinuria [33]. They observed that baseline aldosterone levels
were associated with CKD onset during a 9.5-
The non-genomic pathway, on the other hand, year follow-up of 2345 subjects (OR=1.17, P=
involves aldosterone interacting with receptors 0.047). However, this study did not adjust for
on the cell membrane or other signaling mole- confounding factors like age, sex, hyperten-
cules, directly affecting intracellular signaling sion, and diabetes in the multifactorial regres-
pathways, rapidly regulating cell function and sion model, potentially introducing bias. Sub-
metabolic activities. In terms of vascular regu- sequent studies in various populations yielded
lation, aldosterone exerts its effects mainly by mixed results. A US study [40] involving 9498
binding to HRE and activating the ERK1/2 sig- subjects found no significant association be-
naling pathway, promoting vascular smooth tween plasma aldosterone levels and CKD pre-
muscle cell proliferation and expression of vas- valence, while the Japanese Ohasama study
cular collagen components [34]. This, in turn, [41] reported no correlation between baseline
decreases vascular compliance, constricts aldosterone levels and CKD after a median fol-
small inlet and outlet glomerular arteries, ele- low-up of 9.1 years. Conversely, a German gen-
vates glomerular pressure, and ultimately leads eral population study revealed a negative asso-
to renal fibrosis. In this process, the mediators ciation between plasma aldosterone levels and
of aldosterone-induced renal fibrosis include glomerular filtration rate, with a positive corre-
fibrinogen activator inhibitor 1 (PAI-1) and ni- lation with CKD [42]. Buglioni et al. [43] con-
tric oxide. Moreover, aldosterone induces an ducted a study in 1674 individuals, observing
increase in OPN expression through activator a significant association between aldosterone
protein 1 (AP-1) and NF-κB activation, which and CKD in the cross-sectional analysis; how-
also contributes to the development and pro- ever, this association was not sustained in the
gression of renal fibrosis [35, 36]. longitudinal follow-up after four years.
Furthermore, aldosterone can induce increased The existing literature on the relationship
expression of inflammatory factors and infiltra- between circulating aldosterone levels and kid-
tion of renal inflammatory cells through multi- ney disease in the general population exhibits
ple pathways, as demonstrated by cellular and inconsistencies, particularly regarding the risk
animal experiments. This, in turn, leads to renal of kidney disease development. These discrep-
fibrosis and ultimately manifests as renal inju-
ancies may stem from various factors. First, in
ry. In vivo studies have also shown that aldoste-
the general population, the link between aldo-
rone antagonists can attenuate the damaging
sterone and kidney disease may be weak due
effects of aldosterone on the kidney to some
to most individuals having aldosterone levels
extent.
within the physiological range, resulting in mini-
Clinical study of aldosterone and kidney mal injuring effects. Second, disparities in
disease study locations may introduce biases as aldo-
sterone levels are influenced by both physiolog-
Association between aldosterone and kidney ical and external factors like dietary habits,
disease in the general population potentially contributing to result variations.
Third, inadequate adjustment for confounding
Numerous clinical studies have investigated factors could also contribute to divergent find-
the link between circulating aldosterone levels ings. Despite some studies suggesting a corre-
and kidney injury across diverse populations in lation between aldosterone and kidney dam-
recent years [37, 38]. As our understanding of age, many did not adequately control for known
kidney disease has advanced, it has become confounders, potentially influencing the out-
evident that conventional risk factors may not comes. Moreover, the prevalent use of cross-
entirely account for the occurrence and pro- sectional study designs limits causal inference
gression of kidney disease, suggesting the between aldosterone and kidney damage due
involvement of additional unidentified factors. to the bidirectional relationship between these
For instance, Fox et al. [39] explored the predic- variables. In conclusion, further exploration of
tive value of aldosterone levels for CKD devel- the relationship between circulating aldoste-

4250 Am J Transl Res 2024;16(8):4246-4255

 The renal benefits of mineralocorticoid receptor antagonists

rone levels and renal impairment in the general sion and diabetes mellitus. Despite the availa-
population is warranted, necessitating larger bility of various antihypertensive and hypogly-
sample sizes, longitudinal study designs, and cemic medications with some protective ef-
comprehensive adjustment for confounding fects, the control of kidney disease develop-
factors. ment and progression remains incomplete in
these at-risk groups. Clinical trials have investi-
Relationship between aldosterone and kidney gated the renal benefits of aldosterone an-
disease in different disease populations tagonist therapy. A meta-analysis by Bolignano
et al. [45] examined the impact of aldosterone
The current literature on the relationship be- antagonists in CKD patients. This analysis of
tween aldosterone and kidney disease across 27 randomized controlled trials involving 1549
various patient populations is both limited and subjects revealed that adding spironolactone
inconsistent. Evidence suggests that individu- to ACEIs/ARBs therapy significantly reduced
als with aldosteronism tend to have higher 24-hour urinary protein excretion without
serum creatinine levels, increased urinary pro- affecting glomerular filtration rate. However,
tein excretion, and reduced glomerular filtration aldosterone antagonist treatment increased
rates compared to those with essential hyper- the risk of hyperkalemia and mastocytosis.
tension. Nonetheless, further research is nec- Another meta-analysis focusing on spironolac-
essary to comprehensively understand the tone in diabetic nephropathy patients reported
connection between aldosterone and renal similar outcomes, with a reduction in urinary
function in these patients. The JPAS study in protein excretion but an elevation in blood
Japan highlighted a robust association between potassium levels [46].
elevated plasma aldosterone levels and kidney
disease in primary aldosteronism patients [44]. A recent randomized placebo-controlled trial
Nevertheless, the cross-sectional nature of the evaluating the medium- and long-term efficacy
study precluded causal determinations. Limited of eplerenone in CKD patients demonstrated a
research has explored the link between aldo- decrease in estimated glomerular filtration rate
sterone and kidney disease in populations with (eGFR) levels in both groups initially, with lower
other conditions such as hypertension and dia- levels observed in the eplerenone group at 6
betes, where altered circulating aldosterone months and stable levels thereafter [47]. By the
levels may be present. end of the 36-month study, eGFR levels were
significantly higher in the eplerenone-treated
In summary, primary aldosteronism patients group compared to the placebo group, suggest-
demonstrate a significant association between ing potential long-term renal protection.
plasma aldosterone and kidney damage.
Conversely, in hypertensive individuals with While finerenone has been extensively studied
abnormal glucose metabolism lacking primary in the largest research program on non-steroi-
aldosteronism, plasma aldosterone levels inde- dal MRA, there are other compounds that have
pendently correlate with kidney disease devel- been explored in various contexts. One such
opment. Therefore, targeting aldosterone may compound is esaxerenone, a non-steroidal
hold promise for preventing and managing MRA that has received approval in Japan for
kidney disease in these patients. Nonetheless, managing hypertension and diabetic kidney
further longitudinal investigations are essential disease [48]. In the 12-week double-blind
to assess the relationship between aldoste- Phase III RCT ESAX-HTN, it was found that 2.5
rone and kidney disease progression in diverse mg esaxerenone was noninferior and 5 mg
disease populations, particularly those without esaxerenone was superior to 50 mg eplere-
aldosterone-related conditions. none in lowering blood pressure among 1001
Japanese patients with essential hypertension,
Potential role of mineralocorticoid receptor with comparable rates of adverse events
antagonists on kidney disease observed across the study arms [49]. Fur-
thermore, in the ESAX-DN trial, a 52-week dou-
Aldosterone has been implicated in the pro- ble-blind Phase III RCT involving 455 diabetic
gression of kidney disease, particularly in high- kidney disease (DKD) patients on RAS inhibitor
risk populations with conditions like hyperten- therapy, esaxerenone demonstrated significant

4251 Am J Transl Res 2024;16(8):4246-4255

 The renal benefits of mineralocorticoid receptor antagonists

improvement in albuminuria compared to the prognosis in patients with diabetes and CKD,
placebo group (HR for time to first remission of and its potential for use in other populations
albuminuria: 5.13; 95% CI 3.27, 8.04) [50]. with different diseases deserves exploration in
Additionally, a Phase II dose-finding RCT with future studies. Future research directions could
293 DKD patients revealed that the non-steroi- focus on the efficacy of aldosterone antago-
dal MRA apararenone led to a dose-dependent nists in different patient populations and the
reduction in albuminuria ranging from 37% to broader application of finerenone in the treat-
53%, while the placebo group experienced a ment of kidney diseases, providing more op-
14% increase [51]. There is a growing interest tions and possibilities for the treatment and
in targeting MR activation with enhanced safe- management of kidney diseases.
ty profiles, potentially through MR modulators
that do not impact renal potassium excretion. Acknowledgements
Balcinrenone (AZD9977), one such MR modu-
This work was supported by grants from the
lator, has demonstrated organ protection
National Natural Science Foundation of China
properties without affecting the urinary sodi-
(Grant No. 82260575), the Joint Project on
um/potassium ratio in animal models [52].
Regional High-Incidence Diseases Research
Currently, it is undergoing evaluation against a
of Guangxi Natural Science Foundation (Grant
placebo in the Phase IIb RCT MIRACLE, which is
No. 2024GXNSFAA010337, No. 2024GXNSF-
enrolling 147 patients with heart failure and
AA010316), the Guangxi Key Research and
CKD (NCT04595370).
Development Project (Grant No. Guike AB211-
In summary, MRAs have shown potential in 96022), the Guangxi Science and Technology
managing kidney disease, especially in high- Major Project (Grant No. Guike AA22412, Grant
risk populations. While they effectively reduce No. Guike AA22398), the Major Project of
proteinuria and improve renal function in the Guangxi Innovation Driven (Grant No. Guike
short term, their long-term impact on kidney AA18118016), the Guangxi key Laboratory for
health warrants further exploration through Genomic and Personalized Medicine (Grant No.
larger studies with extended follow-up periods 2022-06535-3317), the Guangxi Medical and
Health Key Discipline Construction Project, the
[53, 54]. The emergence of novel agents like
National Key R&D Program of China (Grant No.
finerenone offers hope for improved outcomes
2017YFC0908000), and the Innovation Project
in patients with diabetes mellitus and CKD,
of Guangxi Graduate Education (Grant No.
emphasizing the ongoing evolution of treat-
YCBZ2024123).
ment strategies for kidney damage [55].
Disclosure of conflict of interest
Conclusions
None.
Preclinical studies have demonstrated the abil-
ity of aldosterone to activate multiple pathways Address correspondence to: Rirong Yang, Center
that lead to renal inflammation and fibrosis. for Genomic and Personalized Medicine, Guangxi
Although preclinical studies have demonstrat- key Laboratory for Genomic and Personalized
ed this, the exact relationship between aldoste- Medicine, Guangxi Collaborative Innovation Center
rone and kidney disease in the general popula- for Genomic and Personalized Medicine, Guangxi
tion remains unclear and requires further in- Medical University, Nanning 530021, Guangxi,
vestigation. In populations at high risk of kidney China. E-mail: [email protected]; Wei Li,
disease, such as hypertensive patients with Department of Nephrology, The Second Affiliated
diabetes, plasma aldosterone levels have been Hospital of Guangxi Medical University, Nanning
found to be independently associated with the 530021, Guangxi, China. E-mail: [email protected].
development of kidney disease. Traditional al- edu.cn; Zengnan Mo, Center for Genomic and
dosterone antagonists, including spironolac- Personalized Medicine, Guangxi key Laboratory for
tone, have shown potential in the long-term Genomic and Personalized Medicine, Guangxi
renal prognosis of these patients, but larger- Collaborative Innovation Center for Genomic and
scale studies are needed for further evaluation. Personalized Medicine, Guangxi Medical University,
Additionally, the novel drug finerenone has Nanning 530021, Guangxi, China. E-mail: mozeng-
shown a favorable renal and cardiovascular [email protected]

4252 Am J Transl Res 2024;16(8):4246-4255

 The renal benefits of mineralocorticoid receptor antagonists

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 The renal benefits of mineralocorticoid receptor antagonists

Table S1. Pathways of action of aldosterone: genomic and non-genomic

Pathway Mechanism Effects
Genomic Aldosterone binds to Regulates gene expression, activates MR, promotes nuclear translocation, binds
mineralocorticoid receptor to hormone response elements (HRE) in target genes, activates or represses gene
(MR) transcription, promotes formation of proton pumps, ion channels, and transporters
MR interacts with Activation of epithelial sodium channels (ENaC), increases sodium-water reabsorp-
co-activators or repressors tion, regulates body fluid volume and blood pressure levels, activates glucocorti-
coid-regulated kinase 1 (SGK1), inhibits ENaC degradation, enhances expression
of pro-fibrotic genes
MR in cardiomyocytes Promotes myocardial hypertrophy
activates ANP pathway
Non-genomic Aldosterone binds to MR or Rapid increase in intracellular calcium levels, activation of tyrosine kinase c-Src,
acts independently transactivation of epidermal growth factor receptor (EGFR), affects signaling
pathways (ERK, PKC, PI3K), activates p38 MAP and NOX 2/4 in vascular smooth
muscle cells, increases collagen synthesis and reactive oxygen species production
Crosstalk with angiotensin Activation of G protein-coupled receptor (GPCR5), involvement of G protein-cou-
II signaling pathways pled receptor kinase 5 (GRK5), potential activation of estrogen receptor GPER in
myocytes and non-myocytes
MR/AT1R system activation Linked to genomic and non-genomic effects, nuclear translocation of GPCR5, cel-
lular hypertrophy

Table S2. Pathways of aldosterone-induced kidney damage: inflammatory and fibrosis

Pathway Mechanism Effects
Inflammatory Induces production of pro-inflamma- Local tissue damage, active inflammation, infiltration of inflammatory
Response tory factors, chemotaxis, recruitment cells, tissue remodeling, extracellular matrix production, collagen deposi-
of immune cells tion, fibrosis
Stimulates production of inflamma- Development of inflammation and fibrosis in cardiovascular system and
tory factors cardiac damage, upregulation of ICAM-1, VCAM-1, COX-2, MCP-1, OPN,
coronary artery inflammation, local ischemia, necrosis
Fibrotic Stimulates transcription of ICAM-1 Renal tract fibrosis and inflammation, alleviation of glomerular injury, up-
Response and CTGF through SGK-1 and NF-κB regulation of NF-κB expression, increased levels of pro-inflammatory fac-
activation tors in kidneys, activation of NLRP3 inflammatory vesicles in podocytes
Activates ERK1/2 signaling pathway Vascular smooth muscle cell proliferation, expression of vascular col-
lagen components, decreased vascular compliance, glomerular pressure
elevation, renal fibrosis
Induces expression of PAI-1 and OPN Mediators of aldosterone-induced renal fibrosis, contribution to renal
through AP-1 and NF-κB activation fibrosis development and progression