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Citation: Carollo, C.; Sorce, A.;
Cirafici, E.; Mulè, G.; Caimi, G.
Sirtuins and Resveratrol in
Cardiorenal Diseases: A Narrative
Review of Mechanisms and
Therapeutic Potential. Nutrients 2025,
17, 1212. https://doi.org/10.3390/
nu17071212
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Review
Sirtuins and Resveratrol in Cardiorenal Diseases: A Narrative
Review of Mechanisms and Therapeutic Potential
Caterina Carollo * , Alessandra Sorce, Emanuele Cirafici , Giuseppe Mulèand Gregorio Caimi
Department of Health Promotion, Mother and Child Care, Internal and Specialistic Medicine, University of
Palermo, 90127 Palermo, Italy; emanuele.cirafici@community.unipa.it (E.C.); giuseppe.mule@unipa.it (G.M.)
*Correspondence: caterina.carollo@unipa.it
Abstract: Aging is a very complex process, and it has been linked with Sirtuins. Sir-
tuin enzymes are a family of deacetylases that are related to caloric restriction and aging
by modulating energy metabolism, genomic stability, and stress resistance. Up to now,
seven sirtuins have been recognized. This narrative review aimed to analyze the liter-
ature produced between January 2005 and March 2025 to evaluate the role of sirtuins
in chronic kidney disease and, as heart and kidney diseases are strictly interrelated, to
explore their role in heart diseases and cardio-renal cross-talk. A reciprocal relationship
between CKD and aging seems to exist since CKD may contribute to premature biologi-
cal aging of different organ systems. SIRTs are involved in the pathophysiology of renal
diseases; their activation can delay the progression of several renal diseases. Notably, an
increasing number of studies linked SIRTs with different CVDs. SIRTs affect the production
of mitochondrial reactive oxygen species (ROS) by modulating mitochondrial function.
The imbalance of SIRT levels may increase the vulnerability to CVDs. SIRTs are involved
in the pathophysiological mechanisms of HFpEF (heart failure with preserved ejection
fraction) through different signaling pathways. Fibrosis is the linkage mechanism between
the heart and kidney in the development of cardio-renal diseases. Current studies on
sirtuins, resveratrol, and cardiorenal disease highlight their potential therapeutic benefits in
regulating blood pressure, kidney function, lipid profiles, and inflammation, making them
a promising area of investigation for improving cardiovascular and renal health outcomes.
However, significant gaps remain. The limited availability of highly selective and potent
sirtuin modulators hampers their clinical translation, as most existing compounds exhibit
poor bioavailability and suboptimal pharmacokinetic properties.
Keywords: sirtuins; SIRTs; aging; CKD; CVD; cardiorenal syndromes; CRS; resveratrol
1. Introduction
Aging is a highly complex and multifactorial process influenced by genetic, environ-
mental, and cellular pathways, involving intricate molecular mechanisms that regulate
cellular homeostasis, metabolic balance, and stress responses [
1
]. Aging is an extraordinar-
ily complex and multifactorial process shaped by an interplay of genetic predisposition,
environmental influences, and cellular pathways. It involves intricate molecular mech-
anisms that regulate cellular homeostasis, metabolic balance, and stress responses. In
recent decades, extensive research has underscored the pivotal role of epigenetic modifica-
tions, mitochondrial dysfunction, telomere attrition, and chronic inflammation—commonly
termed “inflammaging”—in driving age-related physiological decline [2]. These intercon-
nected factors contribute to cellular senescence, impaired tissue function, and increased
susceptibility to age-associated diseases.
Nutrients 2025,17, 1212 https://doi.org/10.3390/nu17071212
Nutrients 2025,17, 1212 2 of 18
Among the key molecular regulators of aging, sirtuins (SIRTs) have garnered signifi-
cant attention. This conserved family of NAD+-dependent proteins plays a crucial role in
cellular stress resistance, metabolic regulation, and genomic stability. Sirtuins are known to
modulate gene expression, DNA repair, mitochondrial function, oxidative stress resistance,
and autophagy—hallmark processes linked to longevity [
3
]. However, while their role in
aging and associated diseases is well established, the relationship between sirtuins and the
aging process is far more intricate than often portrayed.
Aging is not dictated by molecular mechanisms alone; rather, it emerges from a com-
plex interaction between genetic predispositions, environmental exposures, and lifestyle
choices [
4
]. Factors such as diet, physical activity, circadian rhythm regulation, and ex-
posure to toxins or pollutants profoundly influence sirtuin activity. For instance, caloric
restriction and certain bioactive compounds like resveratrol have been shown to activate
SIRT1, promoting longevity-associated pathways [
5
]. Conversely, chronic stress, obesity,
and metabolic disorders can downregulate sirtuin function, accelerating cellular aging and
increasing the risk of age-related diseases such as cardiovascular disease, neurodegenera-
tion, and chronic kidney disease [6,7].
Furthermore, sirtuins do not act in isolation; they operate within a vast regulatory net-
work that includes insulin signaling, AMPK activation, and mTOR inhibition—pathways
that collectively influence lifespan and health span. The interaction between sirtuins and
epigenetic modifications further adds to this complexity, as changes in DNA methylation,
histone acetylation, and chromatin remodeling shape cellular responses to aging [
8
]. Addi-
tionally, sirtuin-mediated mitochondrial maintenance and energy metabolism are closely
linked to the availability of key metabolites such as NAD+, whose levels decline with
age [9].
Given these multifaceted interactions, a more comprehensive approach to studying
sirtuins should consider their dynamic interplay with genetics, environmental stressors,
and lifestyle interventions. Understanding these relationships provides valuable insights
into potential therapeutic strategies aimed at promoting healthy aging and mitigating the
impact of age-related diseases.
Seven sirtuins, listed from one to seven, have been recognized so far. Each shows a
catalytic domain (present in all sirtuins), and different N- and C-ends give each sirtuin
specific biological features [10].
Sirtuins (SIRT1–SIRT7) exhibit distinct intracellular localization, with SIRT1, SIRT6,
and SIRT7 primarily nuclear, SIRT2 cytoplasmic, and SIRT3–SIRT5 mitochondrial, in-
fluencing diverse cellular functions. Their activity is modulated by various activators
such as NAD+, resveratrol, and Piceatannol, and inhibitors like nicotinamide, EX-527 and
SirReal2 [11].
Main SIRTs characteristics like function, intracellular localization, and respective
activators and inhibitors are illustrated in Figure 1.
Sirtuins may promote different post-translational modifications in many different
proteins, so they are actually known as deacetylases [
12
]. Sirtuins’ activity depends on
nicotinamide adenine dinucleotide (NAD
+
). This is very important if we consider that
NAD
+
is a crucial cofactor for many mitochondrial metabolic processes that lead to energy
production. Mitochondria are largely expressed in the heart and kidneys. Mitochondrial
reactive oxygen species (ROS) production leads to altered DNA and electron chain transport,
thus impairing mitochondrial function. This dangerous chain could be counteracted by
healthy mitochondria and selective autophagy of damaged ones, thus explaining the
beneficial effects of caloric restriction [13].
Nutrients 2025,17, 1212 3 of 18
Nutrients 2025, 17, x FOR PEER REVIEW 3 of 19
Figure 1. Main SIRTs characteristics: localization, functions, activators, and inhibitors [11].
Sirtuins may promote dierent post-translational modications in many dierent
proteins, so they are actually known as deacetylases [12]. Sirtuins’ activity depends on
nicotinamide adenine dinucleotide (NAD+). This is very important if we consider that
NAD+ is a crucial cofactor for many mitochondrial metabolic processes that lead to energy
production. Mitochondria are largely expressed in the heart and kidneys. Mitochondrial
reactive oxygen species (ROS) production leads to altered DNA and electron chain
transport, thus impairing mitochondrial function. This dangerous chain could be counter-
acted by healthy mitochondria and selective autophagy of damaged ones, thus explaining
the benecial eects of caloric restriction [13].
The classication of sirtuins as merely NAD+-dependent deacetylase is an oversim-
plication that does not fully capture the complexity of their biological roles. Although
NAD+ is an essential cofactor for the majority of sirtuins, it is not the sole determinant of
their enzymatic activity. Sirtuins are involved in a broader range of cellular processes and
enzymatic modications, extending well beyond deacetylation. This functional diversity
underscores the need to recognize the multifaceted nature of sirtuin biology. While
deacetylation is the most widely studied activity of sirtuins, some members of the sirtuin
family catalyze additional post-translational modications, including ADP-ribosylation
[14] and deacetylation of non-acetyl groups [15]. Notably, SIRT5 is involved in the
deacetylation of succinyl groups [16], highlighting the ability of sirtuins to modulate a
diverse array of acyl groups beyond acetylation. Moreover, SIRT1 and SIRT6 have been
shown to catalyze mono-ADP-ribosylation, a modication that plays a crucial role in DNA
Figure 1. Main SIRTs characteristics: localization, functions, activators, and inhibitors [11].
The classification of sirtuins as merely NAD
+
-dependent deacetylase is an oversim-
plification that does not fully capture the complexity of their biological roles. Although
NAD
+
is an essential cofactor for the majority of sirtuins, it is not the sole determinant of
their enzymatic activity. Sirtuins are involved in a broader range of cellular processes and
enzymatic modifications, extending well beyond deacetylation. This functional diversity
underscores the need to recognize the multifaceted nature of sirtuin biology. While deacety-
lation is the most widely studied activity of sirtuins, some members of the sirtuin family
catalyze additional post-translational modifications, including ADP-ribosylation [
14
] and
deacetylation of non-acetyl groups [
15
]. Notably, SIRT5 is involved in the deacetylation
of succinyl groups [
16
], highlighting the ability of sirtuins to modulate a diverse array of
acyl groups beyond acetylation. Moreover, SIRT1 and SIRT6 have been shown to catalyze
mono-ADP-ribosylation, a modification that plays a crucial role in DNA repair and various
regulatory pathways, further broadening the scope of sirtuin function [17].
In our previous studies, we investigated the role of sirtuins in modulating factors
that accelerate physiological aging, including glucose metabolism, DNA integrity, cancer
development, neurodegenerative disorders, and chronic obstructive pulmonary disease
(COPD) [18].
Building on our previous work and recent findings the current objective is to elucidate
the role of sirtuins as key pathophysiological mediators and potential therapeutic targets in
the progression of chronic kidney disease (CKD). Additionally, recognizing the intricate
Nutrients 2025,17, 1212 4 of 18
interrelationship between cardiovascular and renal dysfunction, we aim to investigate the
involvement of sirtuins in heart diseases, with a particular focus on the cardio-renal axis
and the molecular mechanisms underlying cardio-renal cross-talk.
2. Materials and Methods
This study utilizes a narrative review approach to provide a qualitative and interpre-
tative synthesis of existing literature on the connection between sirtuins and cardiorenal
disease. A comprehensive literature search was performed using Web of Science, PubMed,
and Scopus, covering all articles indexed from January 2005 to March 2025. The search
strategy incorporated keywords such as “sirtuins”, “aging”, “chronic kidney disease”,
“cardiovascular disease”, “resveratrol”, and “cardiorenal syndrome”. After identifying
the initial pool of records, three researchers (CC, AS, and MC) carried out the article
screening process.
3. Sirtuins and Kidney Diseases
In kidney disease, sirtuins influence key pathological mechanisms such as fibrosis,
apoptosis, mitochondrial dysfunction, and inflammation, which contribute to disease
progression [
19
,
20
]. Dysregulation of sirtuin activity has been implicated in acute kidney
injury [
21
], diabetic nephropathy [
22
], and chronic kidney disease [
23
,
24
]. Understanding
the precise roles of sirtuins in renal physiology and pathology may provide new therapeutic
targets for mitigating kidney disease and improving renal function. Regarding renal
physiology, sirtuins’ expression in the kidney and their functions are various.
SIRT1 and SIRT6 play a crucial role in preserving both the structural and functional
integrity of podocytes, which is essential for maintaining the filtration barrier in the kidneys.
In addition to its role in podocyte health, SIRT1 is also involved in the regulation of
endothelial function by modulating endothelial nitric oxide synthase (eNOS), which has a
direct impact on systemic blood pressure [25].
SIRT3 contributes to vascular health by regulating vascular endothelial growth factor
(VEGF), a key factor in maintaining endothelial integrity [
26
]. Within the proximal tubule,
SIRT1, SIRT3, and SIRT5 are essential for mitochondrial function, ensuring that tubular
cells produce adequate ATP to support solute reabsorption [
27
,
28
]. Meanwhile, in the distal
tubules, SIRT1 plays a significant role in regulating sodium balance and water reabsorption
by influencing the α-subunit of the epithelial sodium channel (ENaC) [29].
Moreover, in both the proximal and distal tubules, SIRT7 is involved in maintaining
an acid–base balance and renal electrolyte homeostasis. This is achieved through the
deacetylation of the K+/Cl
−
cotransporter 4 (KCC4), which is crucial for proper renal
ion transport [
30
]. These findings highlight the diverse and essential functions of sirtuins
in kidney physiology, particularly in maintaining cellular homeostasis and overall renal
function. Sirtuins expression in both the glomerular and tubular compartments of the
kidney are illustrated in Figure 2.
3.1. Sirtuins and Acute Kidney Injury
Aging kidneys show an increased vulnerability to ischemia/reperfusion (I/R)-induced
injury, suggesting that sirtuins might play a significant role in the response to I/R. SIRT1
has been shown to confer resistance to kidney injury after I/R [
31
]. Overexpression of SIRT1
reduces kidney injury by activating antioxidant pathways such as the Nrf2/HO-1 signaling
pathway and reducing p53 expression, which subsequently attenuates apoptosis [
31
,
32
].
Additionally, SIRT1 promotes mitochondrial biogenesis, restoring ATP levels and reducing
mitochondrial mass, nitrosative stress, and inflammation, which help protect against I/R
injury. Activators like SRT1720, which stimulate SIRT1, have been shown to improve
Nutrients 2025,17, 1212 5 of 18
renal function following I/R injury by enhancing mitochondrial function and reducing
inflammation [
33
]. The activation of mitochondrial biogenesis through PGC-1
α
is proposed
as a key mechanism for repair after I/R injury [34].
Nutrients 2025, 17, x FOR PEER REVIEW 5 of 19
Figure 2. Sirtuins expression in both the glomerular and tubular compartments of the kidney. SIRT1
and SIRT6 are essential for the structural and functional integrity of podocytes, which helps main-
tain the ltration barrier. SIRT1 also regulates endothelial function by controlling endothelial nitric
oxide synthase (eNOS), impacting systemic blood pressure. SIRT3 regulates vascular endothelial
growth factor (VEGF), playing a role in endothelial integrity. In the proximal tubule, SIRT1, SIRT3,
and SIRT5 preserve mitochondrial function, enabling tubular cells to generate the ATP required for
solute reabsorption. In the distal tubules, SIRT1 is involved in regulating sodium balance and water
reabsorption by controlling the α-subunit of the epithelial sodium channel (ENaC). In both proximal
and distal tubules, SIRT7 regulates the acid–base balance and renal electrolyte handling by deacety-
lating the K+/Cl− cotransporter 4 (KCC4).
3.1. Sirtuins and Acute Kidney Injury
Aging kidneys show an increased vulnerability to ischemia/reperfusion (I/R)-in-
duced injury, suggesting that sirtuins might play a signicant role in the response to I/R.
SIRT1 has been shown to confer resistance to kidney injury after I/R [31]. Overexpression
of SIRT1 reduces kidney injury by activating antioxidant pathways such as the Nrf2/HO-
1 signaling pathway and reducing p53 expression, which subsequently aenuates apop-
tosis [31,32]. Additionally, SIRT1 promotes mitochondrial biogenesis, restoring ATP lev-
els and reducing mitochondrial mass, nitrosative stress, and inammation, which help
protect against I/R injury. Activators like SRT1720, which stimulate SIRT1, have been
shown to improve renal function following I/R injury by enhancing mitochondrial func-
tion and reducing inammation [33]. The activation of mitochondrial biogenesis through
PGC-1α is proposed as a key mechanism for repair after I/R injury [34].
SIRT3, predominantly localized in the mitochondrial matrix, is another key sirtuin
involved in I/R injury. Following I/R, SIRT3 expression increases, and its overexpression
helps protect the kidneys by suppressing superoxide generation [35]. Loss of SIRT3,
Figure 2. Sirtuins expression in both the glomerular and tubular compartments of the kidney. SIRT1
and SIRT6 are essential for the structural and functional integrity of podocytes, which helps maintain
the filtration barrier. SIRT1 also regulates endothelial function by controlling endothelial nitric
oxide synthase (eNOS), impacting systemic blood pressure. SIRT3 regulates vascular endothelial
growth factor (VEGF), playing a role in endothelial integrity. In the proximal tubule, SIRT1, SIRT3,
and SIRT5 preserve mitochondrial function, enabling tubular cells to generate the ATP required
for solute reabsorption. In the distal tubules, SIRT1 is involved in regulating sodium balance and
water reabsorption by controlling the
α
-subunit of the epithelial sodium channel (ENaC). In both
proximal and distal tubules, SIRT7 regulates the acid–base balance and renal electrolyte handling by
deacetylating the K+/Cl−cotransporter 4 (KCC4).
SIRT3, predominantly localized in the mitochondrial matrix, is another key sirtuin
involved in I/R injury. Following I/R, SIRT3 expression increases, and its overexpression
helps protect the kidneys by suppressing superoxide generation [
35
]. Loss of SIRT3,
however, exacerbates kidney injury by impairing mitochondrial homeostasis, a process
that can be rescued through restoration of SIRT3 via the AMPK/PGC-1αpathway [36].
Interestingly, SIRT5 has a distinct role in I/R injury, with loss of SIRT5 function
conferring renoprotective effects. SIRT5 regulates fatty acid oxidation by shifting it from
the mitochondria to peroxisomes, which appears to improve kidney function after I/R [
37
].
Conversely, SIRT6 has been linked to the negative regulation of tubular cell injury and
inflammation during I/R injury, suggesting a protective role [38].
Sirtuins, particularly SIRT1 and SIRT6, have been found to alleviate kidney injury in
sepsis-induced AKI by modulating inflammatory responses and promoting autophagy.
In contrast, the role of SIRT2 in sepsis-induced AKI appears to be detrimental, as the
Nutrients 2025,17, 1212 6 of 18
absence of SIRT2 improves renal function and reduces tubular injury [
39
]. SIRT1 has
also been shown to attenuate contrast-induced nephropathy (CIN), a common cause of
AKI, through its modulation of oxidative stress and apoptosis via the PGC-1
α
/FoxO1
signaling pathway [
40
]. SIRT3 deficiency exacerbates CIN, while activation of the SIRT3-
Nrf2 pathway provides protection [41].
3.2. Sirtuins in Chronic Kidney Disease and Fibrosis
By 2021, a joint statement from the American Society of Nephrology, the European
Renal Association, and the International Society of Nephrology indicated that more than
850 million people suffer from some form of kidney disease. CKD affects between 8%
and 16% of the population worldwide. It is defined by a glomerular filtration rate (GFR)
of less than 60 mL/min/1.73 m
2
, albuminuria of at least 30 mg per 24 h, or markers of
kidney damage (e.g., hematuria or structural abnormalities such as polycystic or dysplastic
kidneys) persisting for more than 3 months [42].
CKD is associated with a great increase in morbidity and mortality and a decrease in
health-related quality of life. The severity of these complications is generally proportional to
the decline in renal function, and it is most evident in patients with end-stage renal disease
(ESRD) [
43
]. Moreover, CKD causes very important economic consequences. In 2023,
in the USA, there was a 40% increase, from USD54.9B to USD76.8B, in expenditures for
individuals with CKD [44].
The risk of CKD increases with age, and elderly patients are overrepresented in the
dialysis population [
45
]. Moreover, a reciprocal relationship between CKD and aging
seems to exist since CKD may contribute to premature biological aging of different organ
systems [
46
] This may result in the occurrence of usually geriatric complications in relatively
young patients with ESRD [
16
]. This phenomenon, referred to as “premature aging”, is due
to the interplay of various biological processes and signaling pathways that drive both renal
injury and systemic age-related dysfunction. One of the primary mechanisms by which
CKD accelerates aging is through the enhanced production of reactive oxygen species
(ROS) and chronic inflammation. Oxidative stress plays a central role in aging and is a key
driver of tissue damage in CKD. Elevated ROS levels contribute to endothelial dysfunction,
inflammation, and fibrosis, which in turn promote the premature aging of organs beyond
the kidney [
47
,
48
]. Telomere shortening is another hallmark of aging and is accelerated
in CKD patients. Shortened telomeres are associated with cellular senescence, a state of
irreversible cell cycle arrest that contributes to tissue dysfunction and aging. In CKD, the
process of cellular senescence is observed in renal cells as well as in other tissues, leading
to impaired tissue repair, increased fibrosis, and functional decline [
49
,
50
]. Mitochondrial
dysfunction is a key feature of both aging and CKD. In CKD, mitochondrial damage results
from increased oxidative stress, altered mitochondrial dynamics (such as mitochondrial
fission), and impaired mitophagy, leading to a decline in cellular energy and function [
51
].
This mitochondrial dysfunction is particularly evident in CKD-related complications such
as cardiovascular disease and skeletal muscle wasting, which are often seen in elderly CKD
patients [
52
]. Endothelial dysfunction is a critical factor in the accelerated aging process in
CKD. In CKD, endothelial cells become dysfunctional due to oxidative stress, inflammation,
and impaired nitric oxide signaling, leading to vascular stiffness and impaired organ
perfusion [
53
]. This is especially relevant in elderly CKD patients who are at higher risk of
developing atherosclerosis and other cardiovascular complications associated with aging.
Fibrosis is a hallmark of nearly all progressive forms of chronic kidney disease (CKD),
regardless of the initial cause [
54
]. This fibrotic progression is closely linked to impaired
NAD+ biosynthesis, which downregulates the activity of sirtuins, including those with
anti-fibrotic roles. In rat models of CKD, it has been shown that NAD+ biosynthesis is
Nutrients 2025,17, 1212 7 of 18
significantly reduced, impairing the functions of SIRTs, which are crucial for combating
fibrosis [55].
Each of the seven sirtuins plays a role in this complex relationship.
Sirtuins (SIRT1, SIRT3, and SIRT6) exert anti-fibrotic effects by modulating key molec-
ular pathways, including TGF
β
/Smad, Wnt/
β
-catenin, Notch, and NF-
κ
B. The TGF
β
(transforming growth factor-
β
) pathway is the primary driver of fibrosis in CKD. When ac-
tivated, TGF
β
binds to its receptors (TGF
β
R1 and TGF
β
R2), leading to the phosphorylation
and activation of Smad2/3, which then forms a complex with Smad4 and translocates to the
nucleus to promote the transcription of pro-fibrotic genes, such as collagen I, fibronectin,
and matrix metalloproteinases (MMPs) [
56
]. The Wnt/
β
-catenin pathway plays a critical
role in kidney fibrosis by regulating epithelial-to-mesenchymal transition (EMT), a process
where renal epithelial cells lose their polarity and acquire a fibroblast-like phenotype,
contributing to ECM accumulation [
57
]. The Notch pathway is another critical regulator
of kidney fibrosis, involved in tubulointerstitial fibrosis and glomerulosclerosis. Upon
ligand binding, Notch intracellular domains (NICDs) translocate to the nucleus and activate
pro-fibrotic genes [
58
]. Inflammation is a major contributor to kidney fibrosis, and the
NF-κB pathway is a key regulator of inflammatory responses in CKD [59].
SIRT1 expression is notably decreased in kidney biopsies from patients with focal
segmental glomerulosclerosis (FSGS) [
60
]. Experimental studies have shown that silencing
SIRT1 exacerbates fibrosis in mice with unilateral ureteral obstruction (UUO), a model of
progressive kidney injury [
61
]. In contrast, stimulating SIRT1 through pharmacological
interventions or genetic manipulation has been found to reduce inflammation and matrix
protein accumulation, thus mitigating fibrosis in experimental models of CKD [62].
The anti-fibrotic activity of SIRT1 is primarily attributed to its ability to inhibit the
TGF
β
signaling pathway by deacetylating Smad3 and Smad4. This action reduces the
transcription of pro-fibrotic genes such as collagen IV, fibronectin, and matrix metallo-
proteinase 7 (MMP7) [
63
]. Additionally, SIRT1 influences endothelial cell function, as
demonstrated by targeted deletion of SIRT1 in the endothelium, which impaired vasorelax-
ation and promoted fibrosis by downregulating MMP14, stimulating the HIF2
α
–Notch1
axis, and releasing proteolytic fragments of the endothelial glycocalyx [64].
SIRT6 also plays a protective role against kidney fibrosis. After fibrotic insults, SIRT6
is upregulated in the kidneys and interacts with
β
-catenin. This complex binds to the
promoters of fibrogenic genes and prevents their transcription through SIRT6-dependent
deacetylation of histone proteins [
65
]. SIRT6 overexpression in mice prevented renal
interstitial fibrosis induced by a high-adenine diet by downregulating HIPK2, which
regulates several pro-fibrotic pathways [66]. In renal tubular cells, the phosphorylation of
SIRT6 by GSK3
β
prevented its degradation, thus supporting its anti-fibrotic actions. SIRT3,
a mitochondrial sirtuin, has been shown to play a role in mitigating fibrosis in multiple
organs, including the kidney. In SIRT3-deficient mice, age-dependent fibrosis in the kidney
is exacerbated due to increased TGF
β
signaling and hyperacetylation of GSK3
β
, which
leads to the activation of Smad3 [
67
]. Additionally, SIRT3-deficient mice exhibited reduced
levels of mitochondrial fusion proteins (Opa1 and Mfn1) and increased levels of Drp1,
leading to mitochondrial fission, a process associated with renal dysfunction and fibrosis
since its early stage [68].
In podocytes, SIRT3 has been shown to deacetylate KLF15, a negative regulator of
extracellular matrix protein synthesis, helping to reduce fibrosis [
69
]. Moreover, SIRT3
inhibits renal calcium oxalate crystal formation by promoting macrophage M2 polariza-
tion via the deacetylation of FOXO1 [
70
] and protects from hyperlipidemia-related renal
injury [71].
Nutrients 2025,17, 1212 8 of 18
3.3. Sirtuins and Hypertensive Nephropathy
Sirtuins, particularly SIRT3 and SIRT6, have been shown to exert protective effects
in the pathogenesis of hypertensive nephropathy through various biological functions
such as antioxidative stress, anti-apoptosis, anti-fibrosis, anti-inflammation, and anti-
mitochondrial injury. The protective mechanisms of these sirtuins are primarily achieved
by regulating protein post-translational modifications (PTMs), signaling pathways, and
transcription factors. Studies using SIRT3 knockout or overexpression mouse models have
demonstrated that SIRT3 plays a critical role in alleviating renal fibrosis and oxidative stress
in hypertensive nephropathy. In SIRT3-deficient mice receiving Angiotensin II (Ang II)
infusion, there was an increase in endothelial mesenchymal transformation (EndoMT) and
reactive oxygen species (ROS), which aggravated renal dysfunction [
72
]. On the other hand,
SIRT3 transgenic endothelial-specific mice (TgEC) exhibited alleviation of Ang II-induced
renal fibrosis, EndoMT, and oxidative stress, indicating that SIRT3 plays a protective role
in mitigating hypertension-induced kidney damage [
73
]. SIRT3 knockout also led to iron
overloading and enhanced ROS formation in renal cells via NADPH oxidase, further
worsening renal fibrosis; in contrast, SIRT3 overexpression protected against kidney injury
induced by Ang II [69,74].
SIRT6 also plays a key protective role in hypertensive nephropathy by regulating pro-
tein PTM, DNA damage, cellular metabolism, and mitochondrial function. In endothelial
cells, SIRT6 prevents injury by inhibiting the NK3 homeobox 2-GATA binding protein 5
signaling pathway through deacetylation of histone H3 lysine 9 (H3K9) [
75
]. Furthermore,
SIRT6 has been shown to alleviate Ang II-mediated inflammation and oxidative damage
induced by Ang II suppressing ROS and enhancing gene expression of Nrf2 and HO-1 [
76
].
3.4. Sirtuins and Diabetic Kidney Disease
One of the most common causes of CKD is diabetes. Diabetic kidney disease (DKD) is
defined by the presence of CKD in a person with diabetes [
30
], and it is considered to be the
leading cause of end-stage renal disease (ESRD) in developed and developing countries [
77
].
Sirtuins play a critical role in the pathogenesis of DKD through their regulatory effects on
various cellular pathways [
78
]. Among them, SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7 have
been demonstrated to exert renoprotective effects during both the initiation and progression
of DKD [
79
–
81
]. These protective actions are mediated through their ability to deacetylate
key target proteins and directly modulate the expression of genes and signaling pathways.
In patients with DKD, SIRT1 expression is significantly downregulated in both serum and
renal tissues, suggesting a strong correlation between its expression levels and kidney
function [
82
]. SIRT1 exerts its protective effects by regulating transcription factors such as
NF-
κ
B and FoxO, thereby reducing inflammation, oxidative stress, and apoptosis; it also in-
fluences key signaling pathways, including AMPK/SIRT1, which promotes autophagy and
mitochondrial function, and TGF-
β
1/Smad3, which mitigates fibrosis [
83
]. Furthermore,
SIRT1 interacts with molecules like NQO1 and glucagon-like peptide-1 to prevent apoptosis
and oxidative stress, ultimately alleviating DKD progression [
84
]. SIRT3 alleviates DKD by
preventing HG-induced apoptosis, reducing ROS production, and activating autophagy
through AMPK/PGC-1
α
signaling [
85
]. SIRT4 protects podocytes by reducing mitochon-
drial ROS and inhibiting NF-
κ
B-mediated inflammation and apoptosis [
86
]. SIRT7 mitigates
podocyte apoptosis and inflammation under diabetic conditions [
87
]. Collectively, these
sirtuins contribute to mitochondrial homeostasis and anti-inflammatory mechanisms, high-
lighting their therapeutic potential in DKD. The roles of SIRT2 and SIRT6 in DKD remain
unclear due to conflicting findings. SIRT2 expression is reported to be both upregulated
and downregulated under hyperglycemia, with its knockdown enhancing cell proliferation
Nutrients 2025,17, 1212 9 of 18
and reducing apoptosis, suggesting a potential role in DKD pathology; meanwhile, SIRT6
is linked to increased TNF-αexpression, suggesting a role in inflammation [22,88,89].
3.5. Sirtuins and Polycystic Kidney Disease
The role of SIRTs in autosomal-dominant polycystic kidney disease (ADPKD) is still
emerging. Studies show that SIRT1 inhibition—either through silencing or pharmacological
means—reduces cyst formation in mice. This negative effect of SIRT1 in ADPKD is linked
to its suppression of Rb and p53, which promotes epithelial cell proliferation and cyst
growth [
90
]. However, a clinical trial testing oral niacinamide, a SIRT inhibitor, in ADPKD
patients showed good safety and tolerability but failed to slow kidney enlargement over
12 months [
91
]. In ADPKD patients compared to healthy subjects, Kurtgoz and coworkers
found that urine SIRT1 levels were significantly lower. In addition, serum SIRT1 levels of
ADPKD patients were higher than control cases, but the difference was not statistically
significant. These findings suggest an impaired SIRT1 metabolism in ADPKD patients,
which might play a role in cysts development [
92
]. SIRT2 is involved in cilia pathophysiol-
ogy and centrosome function that in turn are involved in polycystic kidney disease and
ciliopathy-associated disease progression [
90
]. Moreover, by inhibiting caspase-3 and ROS
generation, it affects apoptosis and oxidative stress [93].
4. Sirtuins and Cardiovascular Diseases
Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke,
are the leading cause of global mortality and a major contributor to disability. The total
number of cardiovascular events almost doubled from 1990 to 2019 [
94
]. Notably, an
increasing number of studies linked SIRTs with different CVDs. SIRTs affect the production
of mitochondrial reactive oxygen species (ROS) by modulating mitochondrial function and
increasing endothelial dysfunction, leading to an increased progression of atherosclerotic
lesions [
95
]. The imbalance of SIRT levels may increase the vulnerability to CVDs, including
heart failure (HF), atherosclerosis, ischemic heart disease, hypertrophic heart disease, and
metabolic disease.
It seems that SIRT1 protects the heart from hypertrophic stimulation, oxidative
stress damage, ROS accumulation, and apoptotic damage. It also could avoid is-
chemic/reperfusion injury, as well as SIRT3 and SIRT6 [
96
–
98
]; SIRT3 exerts a cardio-
protective role by protecting mitochondrial function; evidence suggests that activation of
SIRT6 may be a therapeutic tool to treat atherosclerosis.
The role of SIRTs in atherosclerosis is relatively clear, with main effects in regulating
LDL cholesterol levels, macrophages, foam cells, and endothelial function through various
factors and signaling pathways; SIRT1, SIRT3, and SIRT6 are the sirtuins involved in
protecting against atherosclerosis and cardiac hypertrophy [
99
–
101
]. They also exhibit
a protective role in diabetic cardiomyopathy. Unfortunately, not all SIRT activities are
beneficial. For example, SIRT2 is destructive in I/R injury (its downregulation is protective
against I/R injury [
102
]), and SIRT4 is detrimental to heart hypertrophy and fibrosis [
103
].
SIRTs are involved in the pathophysiological mechanisms of HFpEF (heart failure
with preserved ejection fraction) [
104
]. As summarized by the European Society of
Cardiology [105]
, it is the most significant subtype of HF, and it is primarily character-
ized by left ventricular diastolic dysfunction (LVDD).
The SIRT family has recently been found to be associated with HFpEF development through
different signaling pathways such as the eEF2K/eEF2 pathway, the SIRT1/transmembrane
BAX inhibitor motif, the Sirt3/MnSOD pathway, and the AMPK/PGC-1
α
pathway, causing
endoplasmic reticulum stress, apoptosis, mitophagy, oxidative stress, and mitochondrial
dysfunction [106]. SIRT4, SIRT5, and SIRT7, instead, are downregulated in HF.
Nutrients 2025,17, 1212 10 of 18
5. Sirtuins and Cardio-Renal Diseases
It is well known that fibrosis is also involved in the onset of HF, and it is also recognized
as the linkage mechanism between the heart and kidney in the development of cardio-renal
diseases. Fibrosis arises from the proliferation of fibroblasts and their differentiation to my-
ofibroblasts and subsequent deposition of extracellular matrix (ECM). Another important
factor involved in heart and kidney fibrosis is the endothelial-to-mesenchymal transition
(EndMT) [
107
,
108
], which seems to be an important mechanism leading to glomerular
sclerosis in DKD [
109
]. Several studies have shown that TGF-
β
, through activation of
several signaling pathways (TGF/Smad, Erk, Akt), is the main stimulator and modulator
of EndMT [
110
]. According to previous studies, SIRT1 and SIRT3 (both decreased in TGF-
β
-induced EndMT) seem to be TGF-
β
inhibiting factors [
111
,
112
], so their upregulation
could be a chance to attenuate both cardiac and renal fibrosis, thus mitigating cardio-renal
syndromes, in which fibrosis plays an important role [113].
One of the most important recognized mechanisms leading to cardiorenal syndromes
(CRS) is endothelial dysfunction [
114
–
116
]; indeed, it plays an important role in the patho-
physiology of hypertension, which is considered to be one of the most common risk factors
in the development of both renal and cardiac damage. Guo J et al., in a murine model,
demonstrated that the downregulation of SIRT6 contributes to endothelial dysfunction
and is involved in the pathogenesis of hypertension. The aim of the study was to explore
the role of SIRT6 in the development of hypertension and the molecular mechanisms
involved. It was found that SIRT6 indirectly regulates the expression of GATA5, a tran-
scription factor that regulates blood pressure, by inhibiting Nkx3.2 expression. It is clear
that the downregulation of SIRT6 reduces GATA5 expression, and this leads to endothelial
dysfunction through reduced nitric oxide bioavailability, increased permeability, and subse-
quent hypertension and cardiorenal injury. These findings suggest that SIRT6 upregulation
may be useful to counteract both hypertension and cardiorenal damage by improving
endothelial function.
Mitochondrial dysfunction is another important factor involved in the pathophysiol-
ogy of cardiorenal syndromes; it entails the reduction of glutathione (GSH) levels, increased
inflammation, and altered redox signaling, all of these factors are involved in the genesis of
oxidative stress and subsequential cardiorenal damage. The SIRTs’ role in mitochondrial
impairment emerges from the involvement of SIRT1 and SIRT3 in the AMPK-SIRT1/3-
PGC-1
α
axis in CRS 3 and 4, in which a primary acute or chronic kidney damage leads
to cardiac dysfunction. This axis regulates several mitochondrial pathways, such as fatty
acid oxidation, oxidative phosphorylation (OXPHOS), inflammation, and mitochondrial
ROS production. It was found that the AMPK-SIRT1/3-PGC-1
α
axis is downregulated in
CRS 3 and 4, and it is closely related to mitochondrial impairment; moreover, it seems that
N-acetylcysteine (NAC) has protective effects against oxidative stress and inflammation
thanks to its ability to increase AMPK, SIRT1, and SIRT3 expression. In conclusion, the use
of antioxidants (such as NAC) should be considered as a strategy to reduce cardiorenal
damage through the restoration of the AMPK-SIRT1/3-PGC-1
α
axis activity, exploiting its
ability to mitigate both inflammation and oxidative stress by increasing the expression of
SOD2 (superoxide dismutase) and GPx (glutathione peroxidase) and decreasing NLRP3
inflammasome/IL-1β/IL-18 activation [117].
6. Resveratrol and Cardio-Renal Diseases
After this dissertation, it is clear how sirtuins deserve our attention for their deep
involvement in metabolic and pathophysiological ways of kidney and heart disease so
these enzymes could be hypothesized as therapeutical targets. Different natural SIRT1
agonists showed renoprotective effects in animal models [
118
], and among these, resveratrol
Nutrients 2025,17, 1212 11 of 18
(RSV) and other phenolic compounds have been widely investigated with interesting and
positive results.
Polyphenols, a diverse group of phytochemicals found in various fruits, vegetables,
teas, and wines, have garnered significant attention in recent years for their potential health
benefits, particularly in the context of cardiorenal diseases. These compounds have been
shown to exhibit antioxidant, anti-inflammatory, and vasodilatory effects, which may be
beneficial for cardiovascular and renal health.
RSV has been proven to be useful in treating different chronic diseases through en-
hancing mitochondrial quality [
119
], which is altered in several chronic diseases, such as
Alzheimer’s disease (AD), Parkinson’s disease (PD), cardiovascular disease, obesity, cancer,
and various forms of CKD (including DKD, IgA kidney disease, membranous nephropathy,
and polycystic kidney disease) [
120
]. RSV seems to be able to regulate mitochondrial dy-
namics, mitophagy, endogenous mitochondrial apoptosis, oxidative stress, mitochondrial
membrane homeostasis, respiratory chain function, and mitochondrial quality control,
thus contributing to the delay of the onset of the above-mentioned chronic diseases [
119
].
SIRT1 activated by RSV attenuates ISO-induced cardiac dysfunction and fibrosis by regu-
lating EndMT
in vivo
[
121
]. SIRT1 overexpression suppressed the development of TGF-
β
1-induced EndMT
in vitro
. In this study, it was also shown that P-Smad2/3 expression
was increased in ISO-induced cardiac fibrosis but was attenuated by RSV-activated SIRT1
(perhaps due to SIRT1’s ability to inhibit the nuclear translocation of Smad2/3).
In addition, in CKD patients, resveratrol exerts beneficial, promising effects by modu-
lating SIRT1 levels, oxidative stress, and inflammation.
Nearly 250 clinical trials involving resveratrol are currently in progress or have been
completed, exploring its effects across various medical conditions [
122
]. However, in the
majority of cases where resveratrol has been evaluated, the treatment has not demonstrated
significant therapeutic benefits, often yielding neutral outcomes. While preclinical studies
suggest promising biological effects, translating these findings into clinical success remains
a challenge.
There is substantial variability in study results regarding resveratrol as a natural
SIRT1 activator, which can be attributed to several factors. The transition of SIRT mod-
ulators from research to clinical application has been challenging due to factors such as
insufficient selectivity for specific SIRT isoforms, low potency, poor bioavailability, and
suboptimal pharmacokinetic and pharmacodynamic properties, as well as differences in
clinical trial design and the baseline metabolic characteristics and dietary factors of the
studied populations.
The existing human clinical trials on resveratrol have primarily focused on its safety
profile and bioavailability, consistently indicating that it is well-tolerated but exhibits low
bioavailability. However, only a limited number of studies have investigated whether
resveratrol can replicate the physiological benefits observed in preclinical models [123].
Targeting SIRTs for kidney disease treatment holds significant potential, particularly in
addressing age-related renal conditions. This is evident from the effects of SIRT-activating
compounds (STACs) in experimental settings. Several small-molecule compounds, includ-
ing SRT1720, SRT2104, SRT2183, and SRT3025, have demonstrated the ability to enhance
SIRT1 activity and mitigate renal damage in preclinical models [
106
,
123
,
124
]. Among
them, SRT2104 and SRT3025 have advanced to clinical trials, reflecting their promise as
therapeutic agents. SRT2104, a selective SIRT1 activator, has shown beneficial effects in
metabolic disorders, cardiovascular health, and inflammatory diseases, in addition to its
renal-protective properties [
124
,
125
]. SRT3025, another SIRT1 activator, has been explored
for its role in promoting endothelial function and reducing fibrosis, which are key factors
in kidney disease progression [126,127].
Nutrients 2025,17, 1212 12 of 18
7. Sirtuins Agonists in Cardiorenal Disease
Sirtuins agonists (represented by NAD
+
) have gradually emerged as new treatments
for heart failure. By modulating metabolism, maintaining redox homeostasis, and regulat-
ing immune responses, sirtuins improve heart failure symptoms and prognosis.
More recently, liraglutide, a novel antidiabetic agent, was shown to influence SIRT1
expression in stroke patients, and this finding confirms that sirtuins are worthy of investi-
gation to ameliorate treatment and prognosis of CKD patients, independently of the cause
of primary kidney disease [128].
SGLT2 inhibitors have been demonstrated to upregulate SIRT3 expression. SGLT2
inhibition suppressed epithelial-to-mesenchymal transition and fibrogenesis in kidney prox-
imal tubules; this effect of SGLT2 inhibition was associated with its ability to restore SIRT3
expression and glycolysis [
129
]. This interesting pharmacological activity could be a poten-
tial therapeutical target to prevent cardiac remodeling. Moreover, SGLT2 inhibitors activate
SIRT1/PGC-1
α
/FGF21 pathway through their ability to induce a fasting-like metabolic
and transcriptional paradigm [
130
]. The cardioprotective effects of SGLT2 inhibitors may
also be related to this particular signaling [131].
8. Future Directions
Future research is obviously needed to clarify the role of these molecules and to
enhance their potential therapeutical role in heart and kidney diseases. However, in our
opinion, this topic is worthy of more attention because resveratrol or other sirtuins agonists’
administration could become a useful and safe tool in cardiorenal diseases.
In diabetic rats, the intergenerational treatment with oral resveratrol improved the
functions of the heart, kidney, and brain. The more interesting finding is that resveratrol
treatment increases the second and third generations’ resistance to neurobehavioral changes,
diabetes, and associated cardio-renal dysfunction [132].
It is really interesting to hypothesize similar studies in humans to prove the efficacy
and safety of this natural compound.
A systematic review and meta-analysis analyzed multiple studies on polyphenol
intake and kidney health. The review concluded that higher dietary polyphenol intake
was associated with a lower risk of chronic kidney disease (CKD) and improved renal
function markers among the general population [
133
]. This aligns with findings from
another study [
134
], which demonstrated that higher consumption of flavonoid-rich foods
was inversely related to the incidence of CKD in older adults.
In addition to their effects on blood pressure and kidney function, the anti-
inflammatory properties of polyphenols have been shown to play a crucial role in protecting
against the progression of cardiorenal diseases. A recent study [
135
] explored the impact of
berry polyphenols on inflammatory markers in patients with chronic heart failure. The find-
ings suggested that berry supplementation led to a significant reduction in inflammatory
cytokines and improved cardiac function, highlighting the protective role of polyphenols
in cardiovascular health [136].
9. Conclusions
In summary, emerging research underlines the potential of polyphenols as a promising
dietary intervention for the prevention and management of cardiorenal diseases. Cur-
rent research on sirtuins, resveratrol, and cardiorenal disease highlights their potential
therapeutic benefits on blood pressure, kidney function, lipid profiles, and inflammation,
making them a valuable area of study for improving cardiovascular and renal health
outcomes but also revealing significant gaps. The lack of highly selective and potent
sirtuin modulators limits their clinical translation, as most available compounds exhibit
Nutrients 2025,17, 1212 13 of 18
poor bioavailability and suboptimal pharmacokinetics. Moreover, the precise mechanisms
underlying resveratrol’s cardioprotective and renoprotective effects remain incompletely
understood, particularly regarding its interaction with different sirtuin isoforms. Further
large-scale clinical trials and mechanistic studies are needed to clarify these aspects and
optimize therapeutic strategies.
Author Contributions: Conceptualization, C.C., A.S., G.C., G.M. and E.C.; Investigation: C.C.,
A.S. and E.C.; Writing—original draft, C.C., A.S., G.C., G.M., E.C. and G.C.; Writing—review and
editing, C.C., A.S., G.C., G.M. and E.C. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflicts of interest.
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