Diabetic kidney disease (DKD), a prevalent form of
secondary nephropathy affecting 30-40% of the global diabetic
population, is clinically characterized by persistent
microalbuminuria accompanied by progressive deterioration of
glomerular filtration function (1,2).
The pathophysiological alterations of DKD primarily manifest as
excessive extracellular matrix (ECM) accumulation, sustained
activation of the inflammatory microenvironment, redox
imbalance-mediated oxidative stress and mitochondrial dysfunction
(3) (Fig. 1). Hyperglycemia-induced metabolic
derangements trigger aberrant regulation of key signaling cascades,
such as the AMP-activated protein kinase (AMPK), PI3K/Akt and MAPK
pathways, which collectively orchestrate the molecular mechanisms
driving disease onset and progression (4).
Post-translational modifications (PTMs) are key
epigenetic mechanisms that govern cellular biological processes,
including phosphorylation, acetylation, methylation,
ubiquitination, small ubiquitin-like modifier (SUMO)ylation,
glycosylation, redox modification. Novel PTMs (such as lactylation
and neddylation) have also been identified with the application of
mass spectrometry-proteomics (5). PTMs refer to covalent alterations
occurring in proteins or peptides. These modifications enhance the
functional diversity of the proteome, which is achieved via the
covalent attachment or detachment of regulatory subunits, or
through the degradation of target proteins in an enzyme-dependent
or -independent manner (6).
These processes increase the intricacy of protein modulation by
affecting protein status, subcellular localization, transportation
and communication with other molecules. Consequently, understanding
of the PTM-mediated mechanisms in DKD is key for the discovery of
innovative targets for therapy development. The present review
aimed to summarize the effect of PTMs on cell death, oxidative
stress, mitochondrial dysfunction, inflammation and fibrosis in the
development and progression of DKD.
Phosphorylation is an enzymatic reaction of protein
kinases that mediates the linkage between specific amino acid
residues of target proteins and phosphate groups in ATP (7). Protein kinases and phosphatases
catalyze the transfer or removal, respectively, of phosphate groups
to their substrates, dynamically modulating the function of
proteins through allosteric regulation to activate enzyme activity
(such as Ser/Thr and Tyr residues) or via the engagement of
interaction domains to trigger signal transduction (such as Tyr
residues) (6). Protein
phosphorylation is implicated in numerous processes, including gene
transcription, cell cycle progression, activation of cell signaling
and cell apoptosis. Previous studies have shown that disruption of
phosphorylation contributes to a range of diseases, including
cancer, cardiovascular disease, respiratory illness, immune
imbalance, metabolic disorders and nervous system disease (8-10).
Acetylation is a type of histone modification that
is linked to the pathogenesis of diabetes. Histone acetylation is a
process whereby acetyl groups are transferred to lysine residues,
which alters the charge of histone proteins, facilitating the
binding of transcription factors to gene promoters and promoting
gene expression (11). The
dynamic balance of histone acetylation/deacetylation is regulated
by the coordinated action of histone acetyltransferase (HAT) and
histone deacetylase (HDAC). HATs include GCN5, p300/CBP-associated
factor (PCAF) and the MYST family. At present, four classes of
HDACs have been identified: i) Class I (HDAC1-3 and 8); ii) class
II (HDAC4-7, 9 and 10); iii) class III, sirtuin family (SIRT1-7)
and iv) class IV (HDAC11) (12).
Moreover, acetylation of non-histone proteins has been reported to
serve a key role in multiple cellular processes, including
regulation of gene expression, DNA damage repair, cell cycle
modulation, protein folding, interactions between proteins,
autophagy, signal transduction and cell metabolism (13). Consequently, abnormal acetylation
is involved in the pathogenesis of various diseases, including
DKD.
Protein methylation encompasses two primary
categories: i) Histone methylation and ii) non-histone methylation.
Histone methylation and demethylation modifications typically occur
on the amino terminal lysine or arginine residues of histones, and
are written by histone methyltransferases [such as enhancer of
zeste homologue (EZH)2, G9a and SET7/9) and erased by histone
demethylases [HDMs; such as lysine-specific demethylase (KDM)6A]
(14). Histone methylation
exerts different regulatory effects on genes due to the different
locations of the methylated histone residues. The methylation of
H3K4, H3K36 and H3K79 is typically associated with gene
transcriptional activation, whereas methylation of H3K9, H3K27 and
H4K20 is associated with gene transcriptional suppression (14,15). Apart from methylating histones,
methylation also occurs on non-histone proteins, which is
associated with the pathogenesis of DKD (16). However, the role of non-histone
methylation in DKD requires further exploration.
PTMs exert regulatory effects on all aspects of
protein function, including alteration of the proteolytic stability
of proteins. Ubiquitination, recognized as the primary PTM involved
in governing protein stability, is a reversible process (17). It can either activate or
inactivate proteins and modulate protein-protein interactions via
the ubiquitin-proteasomal system (UPS) (18). Ubiquitination relies on the
conjugation of ubiquitin, mediated by ubiquitin-activating E1
enzyme, ubiquitin-conjugating E2 proteins and ubiquitin-protein E3
ligase, whereas deubiquitinases [such as ubiquitin-specific
protease (USP)14/22 and OTU domain-containing protein 5 (OTUD5)]
remove ubiquitin and counter this process (19,20). As well as proteasomal
degradation, ubiquitination also directs substrate proteins to
participate in cell signaling pathways, such as NF-κB, TGF-β and
Wnt/β-catenin pathways. Ubiquitination is associated with numerous
processes, such as cell proliferation, DNA repair, gene
transcription, protein degradation, apoptosis and signal
transduction (21,22).
SUMOylation is a highly dynamic enzymatic cascade
similar to ubiquitination involved in multiple cellular processes,
including nuclear-cytosolic transport, transcriptional modulation,
apoptosis, regulation of protein stability, cell stress response
and cell cycle regulation (23).
It is a reversible modification associated with the covalent
attachment of SUMO1-5 to substrate proteins (24). The precursor SUMO is processed by
sentrin/SUMO-specific proteases (SENPs) to generate mature SUMOs,
which are conjugated to the target proteins through an enzymatic
cascade catalyzed by SUMO-activating E1 enzyme, SUMO-conjugating E2
enzyme and SUMO E3 ligase (6,23). SUMOylation is reversed by SENPs,
which recognize and remove the SUMO conjugate from the conjugated
proteins (6,23,24).
Hyperglycemia contributes to the pathogenesis of DKD
by disrupting the equilibrium of enzyme-driven glycosylation and
non-enzymatic glycation (NEG). Glycosylation, in which
carbohydrates are attached to specific amino acids, comprises two
primary types: i) N-linked and ii) O-linked protein glycosylation,
including O-linked N-acetylglucosamine glycosylation
(O-GlcNAcylation) (25).
N-linked glycosylation predominantly occurs in the endoplasmic
reticulum (ER) and Golgi apparatus. Through linkage to asparagine
residues of proteins via N-acetylglucosamine, glycans exerts key
roles in protein folding, stability and transportation (26). Adequate N-glycosylation is
crucial for the correct membrane localization of various key
proteins, including nephrin and podocin, enabling the interactions
of these proteins with other molecules, and further maintains the
normal function of the glomerular filtration barrier (27). O-GlcNAcylation is the reversable
addition of the O-GlcNAc moiety of uridine-diphosphate GlcNAc
(UDP-GlcNAc) to serine or threonine residues of proteins
covalently, which is catalyzed by O-GlcNAc transferase (OGT) and
hydrolyzed by O-GlcNAcase (OGA) (28,29). Disruption of this dynamic
equilibrium impacts multiple cell and metabolic processes, such as
transcriptional regulation, ferroptosis and autophagy (30). NEG is an irreversible conjugation
process that reduces sugars onto a free amino group of proteins,
resulting in the formation of initial Schiff's base, an Amadori
product and advanced glycation end products (AGEs) (31). As the role of NEG in DKD has been
summarized by Ma et al (32) and Parwani and Mandal et al
(33), the present review
focused on the role of classical enzyme-driven glycosylation in
DKD.
Redox homeostasis is key for the normal regulation
of cellular processes. Excessive generation of reactive oxygen
species (ROS) and reactive nitrogen species leads to numerous
pathologies, including diabetes complications, cancer, and
cardiovascular and neurodegenerative disease (34). Redox modifications can be divided
into reversible (S-nitrosylation, S-sulfination, S-glutathione,
S-thiothiolate, intermolecular and intramolecular disulfide bonds
and S-acylation) and irreversible (S-sulfoxide and S-sulfination)
modifications, predominantly targeting the thiol groups of cysteine
and methionine residues (6,34,35). Redox modifications occur in
numerous processes, including transcriptional regulation, protein
folding and stability, cell metabolism, antioxidant homeostasis and
signal transduction (36,37).
Succinylation refers to the covalent conjugation of
a succinyl group to the lysine residue of a substrate protein
mediated by a succinyl group donor (11). Lysine succinylation regulates
mitochondrial function, gene transcription, DNA repair and tumor
formation (44).
Histone lysine crotonylation (Kcr) was first
identified as a PTM in 2011, and is primarily associated with
active transcription (45). Kcr
is enzymatically regulated by the dynamic balance between
crotonyltransferases (such as histone crotonyltransferase, p300/CBP
and PCAF) and decrotonylases (such as HDAC1/2/3/8 and SIRT1-3),
similar to writers and erasers in histone acetylation (11,46). Abundant evidence has indicated
that crotonylation is involved in multiple cell processes including
chromatin remodeling, cell cycle progression and cell metabolism
(47,48).
Kbhb is a type of histone lysine acylation first
identified in 2016, which uses β-hydroxybutyrate (BHB) as the
substrate and has a broad impact on cell functions, including the
modulation of gene expression and cell response to starvation
(6). BHB mediates the Kbhb of
histone lysine within the promoters of certain
starvation-associated genes (such as PPAR and insulin signaling
pathways), facilitating rapid adjustment and adaption in response
to metabolic fluctuations (49).
It is facilitated by p300/CBP, and removed by SIRT13 and HDAC1-3
(11).
The pathophysiology of DKD is characterized by
perturbations in renal hemodynamics, excessive oxidative stress and
persistent inflammation (50). A
number of cellular processes contribute to the initiation and
development of DKD, among which oxidative stress is widely
acknowledged as a key driver of cellular injury induced by
hyperglycemia (51,52). Oxidative stress triggers renal
cell apoptosis and the release of proinflammatory factors, and
activates the signaling pathways implicated in renal fibrosis,
culminating in renal fibrosis and the deterioration of glomerular
filtration function (53).
Additionally, studies have indicated that excessive ROS production
induces mitochondrial dysfunction and contributes to the activation
of proinflammatory factors and the initiation of
epithelial-mesenchymal transition (EMT) in DKD (54,55). Collectively, these pathological
factors elicit histological changes to glomeruli and renal tubules,
thereby promoting the formation of DKD (Fig. 2).
Phosphorylation of proteins is a key PTM for
balancing glucose homeostasis, and relies on signaling cascades
mediated by protein kinases and phosphatases. Unc-51-like kinase 1
(ULK1), a key serine/threonine protein kinase in autophagy, is
modulated by AMPK and mTOR (56). The activated AMPK pathway and
activated autophagy protect numerous types of renal cells in
response to high glucose by directly activating ULK1
phosphorylation (57-59). Augmented phosphorylation levels
of PI3K/Akt/mTOR induce renal apoptosis, glomerular injury and
interstitial fibrosis by inhibiting ULK1 phosphorylation (60,61). The MAPK family is associated with
the progression of DKD, and consists of p38 MAPK, JNK and ERK,
which are involved in apoptosis of renal intrinsic cells in DKD
(62-66).
Glycogen synthase kinase 3β (GSK3β) is a highly
conserved, redox-sensitive serine/threonine protein kinase.
Exposure to the diabetic condition leads to elevated expression of
phosphorylated (p)-GSK3β at tyrosine 216 (p-GSK3βY216),
but a decrease in the expression of inhibitory p-GSK3β at serine 9
(67,68). PI3K/Akt signaling inactivates
GSK3β by phosphorylating GSK3β at serine 9 (69). Nrf2 is a key regulator in redox
balance that can translocate into the nucleus and initiate the
transcription of antioxidant genes, such as heme oxygenase-1 (HO-1)
(70). Activated GSK3β directly
phosphorylates Nrf2 and leads to its nuclear exclusion (71). Additionally, GSK3β phosphorylates
Nrf2 at the Tyr568 site and promotes the translocation of Nrf2 out
of the nucleus by increasing Fyn phosphorylation and its nuclear
retention (71). Overactivated
GSK3β phosphorylates Nrf2, thereby facilitating podocyte apoptosis
and senescence in DKD (67,72). In addition, enhanced
p-GSK3βY216 promotes phosphorylation and degradation of
β-catenin, mediating podocyte apoptosis under diabetic conditions
(73).
In addition, alteration of phosphorylation states of
specific proteins participates in the pathogenesis of DKD.
Activation of the JAK/STAT signaling pathway can affect cell
senescence, autophagy, apoptosis and ferroptosis in DKD (74-76). The phosphorylation state of STAT3
is also modulated by diverse regulators. In renal tubular
epithelial cells (RTECs), sulfhydrated SIRT1 induces
dephosphorylation and deacetylation of STAT3, thereby decreasing
high glucose-induced cell apoptosis, oxidative stress, inflammation
response and EMT progression (77). Furthermore, increasing numbers of
phosphorylated proteins have been shown to participate in the
damage of renal cells in DKD (Table
I) (78-87). This research contributes to a
more comprehensive understanding of the pathogenesis of DKD and
provides a theoretical basis for considering PTMs as a therapeutic
target for DKD.
HAT p300/CBP is a key co-transcriptional activator
that regulates the expression of numerous prooxidant,
proinflammatory and profibrotic genes by mediating H3K27
acetylation, and is associated with mediation of
diabetes-accelerated renal damage (88). Numerous targets of p300/CBP
participate in the regulation of DKD development, including
inducible nitric oxide synthase (NOS) and polo-like kinase 1 (PLK1)
(89,90). ACSS2 epigenetically activates
Raptor expression by histone H3K9 acetylation, promoting activation
of the mTOR complex (mTORC)1 pathway and inhibiting podocyte
autophagy (91). Upregulated
acetylation levels of Beclin1 are associated with exacerbation of
podocyte injury in diabetic conditions and a mutation at K414R
suppresses hyperactivated autophagy, thus ameliorating podocyte
impairment, highlighting the key role of PTMs in the pathological
process of DKD (92).
Multiple HDACs regulate the activities of numerous
proteins involved in cell death during the progression of DKD.
Specifically, inhibition of transcription factor EB (TFEB)
deacetylation induced by HDAC6 promotes TFEB activation and
alleviates RTEC damage (93,94). Moreover, HDAC6-mediated
deacetylation of α-tubulin suppresses autophagy and enhances
motility of podocytes in DKD (95). HDAC4 suppresses podocyte
autophagy and promotes podocyte apoptosis by acetylating STAT1
under diabetic conditions (96).
SIRT1 activation can deacetylate forkhead box (Fox)O3a or regulate
the NF-κB signaling pathway, while subsequently suppressing renal
cell apoptosis (97-99). SIRT3 upregulation also
antagonizes hyperglycemia-mediated tubular apoptosis by regulating
the accumulation of ROS and modulating the ROS-sensitive Akt/FoxO
signaling pathway (100). In
parallel, SIRT6 inhibits the transcription of Notch1/4 by
deacetylating histone H3K9, and protects podocytes against
apoptosis and inflammation by enhancing autophagic flux (101). These results indicate that
HDACs serve as potential therapeutic targets in DKD.
Recruitment of EZH2, a methyltransferase that
produces histone H3 lysine 27 tri-methylation (H3K27me3), at the
FoxA1 promoter region promotes podocyte damage and apoptosis in the
early stage of DKD (102,103). Inhibition of EZH2 by GSK126
attenuates podocyte injury and hyperglycemia-induced ferroptosis
(104,105). By contrast, EZH2/H3K27me3
mitigates podocyte pyroptosis in DKD by increasing early growth
response protein 1 (EGR1) in type 1 diabetic nephropathy (T1DN)
(106). Moreover, AGEs induce
downregulation of EZH2 in podocytes and decrease H3K27me3, which in
turn leads to the upregulated expression of pathological factors
(such as TGF-β1 and SNAI1) that contribute to podocyte injury in
late DKD (107). KDM6A, a HDM
that removes the di- and tri-methyl groups from histone H3K27, is
activated in patients with DKD and mice with T1DN (108). Suppression of KDM6A by
administration of GSK-J4 ameliorates the early lesions of db/db
mice, including renal dysfunction, mesangial matrix accumulation,
inflammation and apoptosis (109). The aforementioned studies
indicate that levels of H3K27 are affected by multiple factors,
such as cell types and environment, and the stage of DKD, thereby
changing the transcription of its target genes.
Numerous altered ubiquitination statuses of proteins
are associated with podocyte dysfunction. Specifically, TRIM29
promotes podocyte pyroptosis by interacting with inhibitor of
NF-κBα (IκBα) to mediate its ubiquitination-dependent degradation,
which triggers NF-κB activation (21). In addition, TRIM63 regulates
PPARα ubiquitination and degradation, contributing to podocyte
injury (110). The E3 ligase
c-Cbl binds to podocin and increases the ubiquitination of podocin,
leading to podocyte injury in DKD (111). Moreover, the deubiquitination
of sperm-associated antigen 5 by USP14 activates Akt/mTOR
signaling, exacerbating high glucose-induced autophagy and podocyte
injury (112). The
ubiquitination state of the receptor-interacting protein kinase
(RIPK)1/RIPK3 pathway downregulated by ubiquitin C-terminal
hydrolase L1, a crucial member of the deubiquitination family,
serves a key role in podocyte necroptosis and apoptosis (113).
Lysine 63 ubiquitination (Lys63-Ub) is increased in
the RTECs of DKD, and associated with autophagy deregulation and
apoptosis activation (114).
The apoptosis of RTECs is prevented by eukaryotic translation
initiation factor 2α ubiquitination and degradation mediated by
HMG-CoA reductase degradation 1 (115). Additionally, ARAP1 maintains
persistent epidermal growth factor receptor (EGFR) activation by
decreasing EGFR ubiquitination and subsequently activates
TGF-β/Smad3 and hypoxia inducible factor 1α (HIF-1α) signaling,
causing injury of RTECs and mesangial cells (MCs) (116,117). The aforementioned studies
demonstrate that targets of ubiquitination, such as Lys63-Ub, may
be a promising direction for DKD therapy.
SUMOylation and deSUMOylation serve vital roles in
the pathogenesis of numerous nephropathic diseases (118-120). In DKD, Kruppel-like factor
(KLF)15 upregulates the expression of SUMO1 and enhances the
SUMOylation of P53, subsequently inhibiting the proliferation of
MCs (121). However, the role
of SUMOylation in other aspects of DKD has not yet been
clarified.
Numerous studies have confirmed an increased number
of O-GlcNAc-positive cells in the glomeruli and enhanced staining
in the tubules in DKD (122,123). Hyperglycemia-driven elevation
of O-GlcNAc modification contributes to DKD progression via the
inhibition of Akt phosphorylation, thus abnormally activating
endothelial NOS (eNOS) (124).
A mutually reinforcing cycle is formed between activation of
O-GlcNAcylation and the intrarenal renin-angiotensin-aldosterone
system (RAAS), exacerbating glucose toxicity, while this effect is
inhibited by RAAS blockers via increasing OGA levels (124). Akimoto et al (125) found that aberrant
O-GlcNAcylation of α-actinin 4 and actin impairs cytoskeletal
structure and adhesive function, leading to morphological changes
in podocyte foot processes. This may trigger the early damage to
the glomerular filtration barrier in DKD. Pharmacological
inhibition of O-GlcNAcylation by OSMI1, an inhibitor targeting OGT,
decreases podocyte apoptosis under diabetic conditions (126). Notably, O-GlcNAc modification
exhibits a bidirectional paradox in tubular epithelial cells.
During prolonged fasting conditions in RTECs, it is essential for
renal lipolysis and exerts a protective effect against lipotoxicity
(127). However,
O-GlcNAcylation disrupts the homeostasis of retinol signals in HK2
cells (an immortalized proximal tubule epithelial cell line from
normal adult human kidney) by extensively modifying the key
molecules in the retinol signaling pathway, such as signaling
receptor and transporter of retinol 6 and retinaldehyde
dehydrogenases 1 (128).
Moreover, diabetic conditions promote OGT-mediated O-GlcNAcylation
of acyl-CoA synthetase long chain family member 4 (ACSL4), thereby
stabilizing ACSL4 and facilitating tubular ferroptosis in DKD
(129). This functional
discrepancy may be attributed to modification targets, cell type
and microenvironmental metabolic status. Additionally, as a subtype
of glycosylation, inhibition of core fucosylation mitigates renal
pathological changes, renal fibrosis and podocyte injury by
downregulating the phosphorylation of Smad2/3 and ERK (130). Targeting protein
O-GlcNAcylation may be a promising therapeutic approach for
rescuing DKD progression.
Lysine succinylation is a naturally occurring PTM
that alters the stability and function of substrate proteins. This
modification is modulated by enzymes such as SIRT5 and serves a
pivotal role in the pathogenesis of DKD. For example, upregulation
of SIRT5 inhibits the succinylation of NIMA-related kinase 7
(NEK7), disrupts the interaction between NEK7 and NOD-like receptor
protein 3 (NLRP3), and suppresses podocyte pyroptosis and oxidative
stress-induced injury under hyperglycemia (139). However, whether protein
succinylation is involved in the cell cycle of other renal cells
remains unclear.
The PI3K/Akt pathway modulates FoxO3a activity by
phosphorylating its three residues (Thr32, Ser253 and Ser315) and
excludes FoxO3a from the nucleus (140). Klotho prevents podocyte injury
against palmitate-induced oxidative stress by decreasing the
phosphorylation of FoxO3a, promoting its nuclear translocation and
upregulating the expression of antioxidants, including manganese
superoxide dismutase (MnSOD) (140). However, in streptozotocin
(STZ)-induced rats, activation of the PI3K/Akt/FoxO3 pathway
alleviates inflammation and oxidative stress in MCs (141). Furthermore, activation of the
AMPK/SIRT1/PPARγ coactivator 1α (PGC1α) pathway mitigates oxidative
stress in db/db mice (142).
Additionally, GSK3β knockdown enhances the antioxidant response
driven by Nrf2 and suppresses oxidative stress, leading to the
alleviation of oxidative stress and podocyte injury (67). Specifically, the elevated
phosphorylation of GSK3β at serine 9 reduces the protein stability
of GSK3β and diminishes its inhibitory effect on Nrf2, protecting
podocytes and RTECs from oxidative stress (67,143). The insulin receptor (IR) is key
for insulin action. Protein tyrosine-phosphatase 1B (PTP1B)
attenuates insulin signaling by dephosphorylating IR and IR
substrate 1, and knockdown of PTP1B protects podocytes from ER
stress by improving insulin sensitivity (144). Targeting protein kinases and
phosphatases may provide more options for DKD treatment.
Members of the SIRT family serve a pivotal role in
DKD pathogenesis. Activation of the SIRT1/PGC1α/Nrf1 and
SIRT1/NF-κB pathways effectively attenuates DKD, induces autophagic
flux, mitigates oxidative stress and alleviates mitochondrial
dysfunction in podocytes (77,145,146). Moreover, SIRT1 can interact
with ACSS2. ACSS2 promotes mitochondrial oxidative stress and
triggers renal tubular inflammation in DKD by modulating the
SIRT1/carbohydrate responsive element binding protein (ChREBP)
pathway (147). Polysulfides
can attenuate diabetic renal pathological lesions via inactivation
of p65 NF-κB and STAT3 phosphorylation/acetylation by sulfhydrating
SIRT1, thereby reducing high glucose-induced oxidative stress, cell
apoptosis, inflammation and EMT (77). Furthermore, the enhancement of
mitochondrial oxidative stress in DKD is mediated by the reduction
of SIRT3 activity and a subsequent increase in acetylated
isocitrate dehydrogenase 2/SOD2 (148). General control of amino acid
synthesis 5-like 1-mediated acetylation of MnSOD also exacerbates
oxidative stress-induced renal injury in DKD (149). The aforementioned studies
demonstrate the key role of the SIRT family in response to
oxidative stress in DKD.
Numerous alterations in the levels of proteins
involved in oxidative stress are regulated by the alteration of
histone methylation status. Expression of monocyte chemoattractant
protein-1 (MCP-1) is elevated due to the recruitment of SET7/9 and
H3K4me1 to its promoters in db/db mice (150). Decreased levels of HIF-1α
suppress oxidative stress and inflammation via HDM KDM3A in human
umbilical vein endothelial cells exposed to hypoxia and diabetic
conditions (151). Siddiqi
et al (152)
demonstrated that inhibition of EZH2 with DZNep can increase
podocyte injury, oxidative stress and proteinuria in diabetic rats.
Moreover, S-adenosylhomocysteine hydrolase inhibition induces
podocyte injury and oxidative stress via the
EZH2/EGR1/thioredoxin-interacting protein/NLRP3 signaling cascade
in STZ-induced T1DN mice (153). At present, the fundamental
mechanism by which EZH2 serves different roles in various DKD
models and cells remains unclear. Due to the involvement of
multiple cell types in the pathogenesis of DKD and the cell
context-specific gene regulation mediated by EZH2, EZH2 may serve a
dual role in different renal cells in DKD (154).
Hyperglycemia prompts Von Hippel-Lindau tumor
suppressor E3 ubiquitin ligase to ubiquitinate glucose-6-phosphate
dehydrogenase, leading to ROS production and podocyte injury
(155). Moreover, under
diabetic conditions, sustained activation of PH domain and
leucine-rich repeat protein phosphatase 1 promotes the nuclear
retention of FoxO1 via prevention of its ubiquitination, inducing
aberrations in renal gluconeogenesis and the activation of the
apoptotic cascade, and exacerbating oxidative stress in diabetic
rats (156). Oxidative stress
and apoptosis are decreased in RTECs by promoting SIRT1 expression
via suppressing its ubiquitination (157). Moreover, the phosphorylation of
c-Cbl at Tyr731 facilitates the combination of c-Cbl and SIRT1,
which triggers polyubiquitination of SIRT1 by c-Cbl and promotes
SIRT1 degradation, decreasing the antioxidant effects of FoxO3a in
DKD (158). Connexin32 (Cx32)
upregulates SIRT1 expression by inhibiting the ubiquitination of
Lys335 of SIRT1 by suppressing Smad specific E3 ubiquitin protein
ligase 1 (Smurf1), thus alleviating oxidative stress in DKD
(157). In addition, Cx32
decreases renal oxidative stress levels and ameliorates the
pathological progression of diabetic renal fibrosis by promoting
NADPH oxidase 4 polyubiquitination and degradation (159). Nrf2 is an important antioxidant
in response to oxidative stress. Suppression of the ubiquitination
of Nrf2 ameliorates experimental DKD through antioxidation and
regulation of the Keap1/Nrf2 signaling pathway (160,161). Additionally, ubiquitination
participates in ferroptosis induced by oxidative stress. Ginkgolide
B alleviates oxidative stress and ferroptosis by inhibiting
glutathione peroxidase (GPX)4 ubiquitination to improve changes in
renal structure in mice with DKD (162). Stimulator of interferon genes
protein inhibition alleviates ferroptosis and oxidative stress in
DKD via stabilization of ferroportin 1 (FPN1) protein levels by
decreasing FPN1 ubiquitination for proteasomal degradation
(163). In addition,
2-deoxy-d-ribose induces ferroptosis in RTECs by degrading the
cystine/glutamate antiporter SLC7A11 protein via the UPS, resulting
in decreased intracellular cystine uptake (164). These findings underscore the
key role of ubiquitination and deubiquitination in DKD development,
and highlight the potential therapeutic targets.
In early stage DKD, ectonucleoside triphosphate
diphosphohydrolase 5 (ENTPD5), a nucleotide hydrolase located in
the ER, modulates the N-glycosylation of proteins and facilitates
renal cell proliferation (165). Separately, in late stage DKD,
sustained hyperglycemia activates the hexosamine biosynthesis
pathway to increase the levels of UDP-GlcNAc, which triggers a
feedback mechanism that suppresses transcription factor SP1
activity and downregulates ENTPD5 expression, aggravating ER stress
(165). Additionally,
O-GlcNAcylation of the mineralocorticoid receptor directly enhances
both the protein abundance levels and transcriptional activity of
the receptor under diabetic conditions (166). These findings provide novel
directions for the diagnosis and targets of DKD.
Hypoglutathionemia and elevated oxidative stress
levels contribute to the early biochemical abnormalities in
diabetes (167). Additionally,
reactive carbonyl derivate levels increase in patients with
diabetes, and this elevation is more pronounced in diabetic
patients undergoing hemodialysis, suggesting that both diabetic
state and hemodialysis contribute to the enhancement of protein
oxidation (168).
A previous study showed that K99 succinylation of
hydroxysteroid 17β dehydrogenase 10 (HSD17B10) maintains
mitochondrial RNA ribonuclease P (RNase P) stability (169). Astragaloside IV alleviates
hyperglycemia-induced oxidative stress and mitochondrial
dysfunction in HK2 cells by upregulating carnitine
palmitoyltransferase 1A-mediated K99 succinylation of HSD17B10 to
maintain RNase P activity (169).
Extensive alterations of cell signaling pathways
serve a broad role in maintaining mitochondrial homeostasis and
optimizing oxidative phosphorylation. Inactivated AMPK and PI3K/Akt
signaling and abnormal activation of the JNK pathway participate in
mitochondrial dysfunction under diabetic conditions, modifying
mitochondrial dynamic homeostasis and energy metabolism disorder in
DKD (170-174). Finerenone treatment can reduce
mitochondrial fragmentation and restore mitophagy via PI3K/Akt/eNOS
signaling in HK2 cells exposed to diabetic conditions and tubular
cells of mice with DKD (172).
In addition, elevated SIRT1 phosphorylation at Ser47 is associated
with mitochondrial dysfunction in podocytes (175). Inhibiting SIRT1
phosphorylation-mediated ubiquitin-proteasome degradation restores
the capacity of SIRT1 to promote PGC1α deacetylation and nuclear
translocation, and thereby upregulates genes associated with
mitochondrial biosynthesis and antioxidant defense in DKD (176).
Phosphorylation of multiple proteins causes
disruption of mitochondrial dynamics and leads to loss of
mitochondrial voltage potential under high-glucose conditions.
Dynamin-related protein 1 (Drp1) is a key regulator of
mitochondrial fission. Cyclin-dependent kinase 5 phosphorylates
Drp1 at Ser616 and thus produces excessive ROS, leading to EMT
progression in HK2 cells (177). Enhanced phosphorylation of Drp1
at Ser637 (p-Drp1Ser637) by Rho-associated coiled
coil-containing protein kinase 1 promotes the transposition of Drp1
to the mitochondrial surface and accounts for excessive
mitochondrial fission in mouse podocytes (178-180). By contrast, resveratrol
decreases Drp1 levels while increasing p-Drp1Ser637
levels, blocking mitochondrial fission in MCs by inhibition of
phosphodiesterase-4D/protein kinase A signaling (181). The functional consequences of
serine phosphorylation of Drp1 may be dependent on cell type and
stimulation. Mitophagy is a specialized form of autophagy that
mediates the selective elimination of damaged or dysfunctional
mitochondria (182). The
phosphorylated form of FUN14 domain-containing 1 (FUNDC1) inhibits
the induction of mitophagy by blocking the interaction between the
FUNDC1 LC3-interacting region and LC3 (183,184). In addition, activated Src
kinase serves as a negative modulator of mitophagy in DKD by
inducing the phosphorylation of FUNDC1 at Tyr18, which impairs the
ability of podocytes to clear damaged mitochondria (185). Studies have demonstrated the
key role of aberrant protein phosphorylation in the progression of
DKD (Table II) (81,186-190). However, further validation at
different stages of human DKD are needed to fully understand the
impact of PTMs.
Protein acetylation is a key component of diverse
metabolic reactions. SIRT1 sustains mitochondrial homeostasis by
mediating mitochondrial biogenesis and mitophagy in DKD (191,192). It has been hypothesized that
the SIRT3/SOD2/GPX4 signaling pathway participates in the
regulation of ferroptosis in DKD via maintenance of mitochondrial
redox homeostasis (193). SIRT6
upregulation alleviates mitochondrial dysfunction and podocyte
apoptosis via AMPK activation mediated by its deacetylation of H3K9
and H3K56 (194). In addition,
activation of SIRT1 exerts a renoprotective role in restoring
mitochondrial homeostasis, providing a preclinical research basis
for small molecule drugs targeting the SIRT family.
TRIM22, a E3 ubiquitin ligase, is highly expressed
in patients with DKD, interacts with optic atrophy 1 and induces
its ubiquitination, thus altering mitochondrial fusion-associated
proteins involved in respiration/ATP synthesis, influencing ROS
production and mitochondrial function in DKD (195). Long non-coding RNA PVT1 is
involved in mitochondrial dysfunction by interacting with TRIM56 at
the post-transcriptional level to induce AMPK ubiquitination,
leading to aberrant mitochondrial biology and increasing
mitochondrial DNA leakage in podocytes in DKD (196). Additionally, interference with
Smurf2 inhibits both RUNX family transcription factor 3
ubiquitination and the TLR4/NF-κB signaling pathway, which
alleviates mitochondrial dysfunction and tubular injury (197). Another E3 ubiquitin ligase,
Cullin3, directly interacts with mitochondrial ribosomal protein
L12 to induce its ubiquitination, resulting in mitochondrial
biosynthesis dysfunction in RTECs (198). However, the effect of
ubiquitination on the mitochondrial homeostasis of MCs and
endothelial cells needs further investigation.
DeSUMOylation of RNA binding motif protein X-linked
serves a key role in determining the microRNA (miRNA/miR)
composition of renal cell exosomes, which prevents the protective
miRNAs from inhibiting mitochondrial damage in DKD (199).
In chronic diabetes, mitochondrial proteins are
susceptible to PTMs triggered by glycation and oxidation. Oxidative
and nitrosative stresses promote mitochondrial oxidative
dysfunction in STZ-induced diabetic rats (200). Carbonyl-mediated modifications
selectively target key protein components of major mitochondrial
cycles, including oxidative phosphorylation and fatty acid
β-oxidation (201).
Methylglyoxal, a dicarbonyl compound that accumulates to high
levels in the hyperglycemic environment, exerts an inhibitory
impact on both the tricarboxylic acid cycle and the electron
respiratory chain (202).
Notably, such modifications are specific to certain mitochondrial
proteins and trigger disturbances in mitochondria involved in renal
cellular toxicity and the progression of DKD (202).
The expression of lysine lactylation is notably
elevated in renal tissues from patients with diabetes as well as
db/db mice (43,203,204). Lactylation of acyl-CoA
synthetase family member 2 at lysine 182 contributes to tubular
mitochondrial dysfunction, which accelerates the progression of DKD
(203). However, research on
the roles of lactylation in other renal cell types is lacking.
NF-κB, interacting with IκB and IκB kinase (IKK),
is a key intracellular molecule regulating inflammation and is
abnormally activated in DKD (205,206). FoxM1 transcriptionally
activates SIRT4, and suppresses phosphorylation of NF-κB (Ser536)
and the levels of NLRP3 inflammasome to ameliorate renal damage and
podocyte pyroptosis in DKD (207). Inflammation in DKD is decreased
by activation of the Nrf2-mediated antioxidant pathway and
inhibition of the MAPK-mediated inflammatory pathway, such as
ERK1/2, JNK and MAPK (205,208,209). Treatment with salidroside
triggers the phosphorylation of Akt and GSK3β; suppressed
expression of p-Akt (Ser473) and p-GSK3β (Ser9) inhibits oxidative
stress and inflammation in DKD rats (210). Upregulated phosphorylation of
SH2 domain-containing protein-tyrosine phosphatase-2 (SHP2) is
detected in macrophages in both diabetic patients and mouse models
(211,212). Macrophage SHP2 deficiency
alleviates DKD via the suppression of MAPK/NF-κB-dependent
inflammation, subsequently attenuating renal dysfunction, collagen
deposition, fibrosis and inflammatory response in STZ-treated mice
(211). Dephosphorylation of
STAT3 (Tyr705) ameliorates tubulointerstitial inflammation and
glomerulosclerosis in DKD (213,214). Monitoring the dynamic changes
of the phosphorylated status of proteins during DKD progression may
improve understanding of the pathogenesis of DKD.
High-glucose stimulation increases H3K9/14Ac at the
receptor for AGEs, plasminogen activator inhibitor-1 and MCP-1
promoters, performing key roles in rat MCs in DKD, whereas losartan
reverses the H3K9/14Ac marks at targeted genes (215). PCAF serves an essential role in
regulating inflammatory molecules through H3K18ac, providing a
potential therapeutic target for inflammation-associated renal
diseases (216-218). HDACs also participate in the
inflammatory response in DKD. Apelin-13 inhibits diabetes-induced
elevation of inflammatory factors and histone hyperacetylation by
upregulation of HDAC1 (219).
Gene silencing of HDAC4 decreases the inflammatory response and
apoptosis induced by hyperglycemia in podocytes (96). Upregulation of SIRT1 inhibits
inflammation through decreasing the induction of inflammatory
cytokines and reducing acetylated-NF-κB (220-223). SIRT6 protects podocytes from
inflammation by inhibiting the Notch pathway (101). Moreover, upregulation of SIRT7
decreases inflammation and improves renal function in glomerular
endothelial cells by regulating the H3K18ac level of
death-associated protein kinase-3 (224). These findings support the
impact of acetylation on DKD and the potential mechanisms of
existing therapeutic drugs, such as losartan.
Different histone modifications are involved in the
inflammatory response in DKD. SET7/9 and H3K4me1 expression are
markedly increased, whereas H3K9me2 and H3K9me3 are decreased by
inflammation induced by hyperglycemia (225,226). Moreover, the diabetic
environment attenuates SET domain-containing protein 8 (SETD8)
levels, as well as their downstream target H4K20me1. Upregulation
of H4K20me1 inhibits endothelial inflammation in DKD by occupying
the promoter regions of diverse target genes, including IL-1
receptor-associated kinase 1, Wnt family member 5A and PTP1B
(227-229). Additionally, yes-associated
protein 1 promotes hyperglycemia-induced inflammation and ECM
deposition by triggering the activation of NF-κB/jumonji
domain-containing protein-3 signaling in MCs (230). In addition, KDM6A regulates the
transcription of inflammatory genes in a manner dependent on its
demethylase activity (109).
These results support that epigenetic alternations are associated
with sustained pro-inflammatory pathways and partly explain the
phenomenon of 'hyperglycemic memory' in DKD. This refers to the
persistent susceptibility of diabetic patients to develop
complications stemming from early hyperglycemic exposure, even
following effective implementation of blood glucose control
(231).
Ubiquitin-modifying enzymes and deubiquitinases act
in conjunction to regulate the transmission of intracellular
ubiquitin signaling to maintain normal cell activities. OTUD5, a
deubiquitinating enzyme, deubiquitinates K63-linked TGF-β-activated
kinase 1 (TAK1) at the K158 site through its active site C224,
which prevents TAK1 phosphorylation and decreases downstream
inflammatory responses in podocytes during DKD (232). E3 ubiquitin ligase speckle-type
BTB-POZ protein promotes NLRP3 degradation by elevating K48-linked
polyubiquitination of NLRP3 (233). TGF-β1 is profibrogenic in renal
fibrosis (234). Latent TGF-β1,
unlike the active form of TGF-β1, protects against inflammation and
fibrosis by blocking the E3-ligase Arkadia-mediated Smad7 ubiquitin
proteasomal degradation pathway in STZ-induced T1DN (234). Obstruction of ubiquitin
degradation of IKK induced by decreased ubiquitin ligase NEDD4L and
inhibition of TNF receptor-associated factor 6 K63
polyubiquitination mediated by USP25 can decrease the activation of
NF-κB and relieve inflammation (19,235). Parkin inhibits pathological
progression of DKD by promoting the ubiquitination of GATA-binding
protein 4 (GATA4) and downregulating GATA4/growth arrest-specific
protein 1 signaling to inhibit premature senescence, renal
inflammation and fibrosis (236). The aforementioned studies
demonstrate that protein ubiquitination performs an important role
in inflammation in DKD.
In diabetic mice, the expression of SENP6 is
decreased in glomerular tissue; this downregulation exacerbates
injury to the glomerular filtration barrier. Mechanistically, SENP6
enhances the ubiquitination of the Notch1 intracellular domain
(N1ICD) by deSUMOylating Notch1, subsequently reducing N1ICD and
inhibiting Notch1 signaling activation in podocytes (237). Moreover, SENP6 deSUMOylates
KDM6A and decreases the binding affinity of KDM6A to endothelin-1
(Edn1) via upregulation of H3K27me2/3 at its promoter (237). Numerous studies have indicated
that hyperglycemia-induced activation of NF-κB inflammatory
signaling is mediated by the SUMO E3 ligase protein inhibitor of
activated STAT y and IκBα SUMOylation (238,239). These findings indicate that the
combined effect of various PTMs regulate the pathogenesis of
DKD.
Protein glycosylation serves an important role in
protein stability, binding, folding and activity, and is a key PTM
of proteins. In mouse kidney endothelial cells, hyperglycemia
causes increased methylglyoxal modification of the corepressor
mSin3A, which results in increased recruitment of OGT and enhanced
O-GlcNAcylation of Sp3 (240).
This modification of Sp3 causes an increase in angiopoietin 2
expression, sensitizing microvascular endothelial cells to the
proinflammatory effects of TNFα (240).
TGF-β1 induces profibrotic and inflammatory genes,
which serve key roles in glomerular dysfunction and the mesangial
matrix expansion associated with DKD (242,243). Multiple protein kinases and
phosphatases have an essential role in renal fibrosis. TGF-β1
stimulation results in the phosphorylation/activation of PKCβII, a
direct substrate of mTORC2, thus modulating renal fibrosis in DKD
(244). Activation of AMPK and
Akt signaling alleviates renal injury and fibrosis in DKD (245-247). Activation of MAPK signaling
aggravates fibrosis under diabetic conditions (248-250). Activation of the GSK3β and
Nrf2/HO-1 pathways also causes inhibitory regulation of EMT and
exerts anti-renal fibrosis activity, delaying the progression of
DKD (251,252). The suppression of
phosphorylation of EGFR and NF-κB are involved in amelioration of
renal tubulointerstitial fibrosis (253-255). Targeting shared profibrotic
pathways via modulation of protein phosphorylation may serve as a
novel therapeutic strategy for DKD (Table III) (130,190,256-260).
Different acetylated states of proteins perform
different functions. For example, p300-dependent H3K27 acetylation
on the PLK1 gene promoter ameliorates renal fibrosis of DKD
(90). Moreover, sterol
regulatory element-binding transcription factor 1a K333 acetylation
mediated by the acetyltransferase CBP is key for Smad3 association
and they cooperatively mediate TGF-β transcriptional responses
(261). In addition, numerous
deacetylases contribute to renal fibrosis in DKD. HDAC2 serves a
key role in the development of ECM accumulation, EMT and renal
interstitial fibrosis in diabetic kidneys by regulating the
acetylation of substrates, including Edn1 and miR-205 (262-264). SIRT1 activation markedly
suppresses endothelial-mesenchymal transition (EndMT) progression,
and attenuates albuminuria and glomerulopathy via regulation of the
acetylation of NF-κB, FoxO1 and FoxO3a (265-267). SIRT3 deficiency in endothelial
cells stimulates TGF-β/Smad3-dependent mesenchymal transformation
in RTECs (268). SIRT6 has been
demonstrated to directly interact with Smad3, a key downstream
mediator of TGF-β, and inhibits its nuclear accumulation and
transcriptional activity by deacetylating it in HK2 cells (269). Furthermore, FoxO3a exerts a
renoprotective effect against diabetic kidney injury via the
SIRT6/Smad3 pathway (Table
III) (269,270). These studies reveal the vital
role of imbalanced acetylation in renal fibrosis in DKD.
EZH2/H3K27me3 recruitment at the promoters of
profibrotic genes is downregulated in rat MCs in T1DN and
reciprocally upregulates expression of these profibrotic genes,
such as connective tissue growth factor and Serpine1 (271). Moreover, EZH2 alleviates the
progression of renal interstitial fibrosis in T1DN by regulating
its downstream genes, such as MMP9 (272). In type 2 diabetic nephropathy,
OGT stabilizes EZH2 by promoting its glycosylation and then
inhibiting MC hyperproliferation and fibrosis by enhancing the
enrichment of EZH2/H3K27me3 in the hairy and enhancer of split 1
promoter (273). However, the
role of EZH2 in DKD remains controversial. In early DKD, enhanced
expression of EZH2 is associated with decreased DEPTOR levels and
increased mTOR activity, inducing MC hypertrophy and matrix
expansion (274). Under
diabetic conditions, recruitment of EZH2 inhibits SOX6, induces
cell proliferation, fibrosis and inflammatory cytokine release in
MCs (275). The method used to
establish DKD models and context-dependent factors affects the
function of EZH2 in renal fibrosis. To explain the role of EZH2 in
renal fibrosis, the association between EZH2 expression and
histological characteristics of patients with DKD should be
assessed.
The enhanced recruitment of SET7/9 and elevated
H3K4me at the p21 promoter, concurrent with the decreased H3K9me
level are observed in the glomeruli of diabetic rats, resulting in
increased mesangial hypertrophy (276). Histone H2AK119
mono-ubiquitination (H2AK119-Ub) downregulates SET7/9 (277). Genetic suppression of SET7/9
decreases profibrotic gene expression and prevents EndMT by
regulating insulin-like growth factor-binding protein 5 (278,279). Additionally, SETD8/H4K20me1
regulates EndMT in DKD by modulating methylation of its downstream
targets, such as profilin 2 and enolase 1 (280-282). However, additional studies are
required to examine the effects of SET7/9 and SETD8 in other cell
types in the progression of DKD.
Beyond methyltransferases that act on the lysine
sites of proteins, elevated protein arginine methyltransferase 1
expression activates activating transcription factor 6 by
recruiting H4R3me2as to the promoter, promoting ER stress and EMT
activation in HK2 cells (283).
In addition, demethylases are associated with renal
fibrosis. Expression of fibrotic proteins and dickkopf-1 is
negatively regulated by the KDM6A inhibitor GSK-J4, attenuating
glomerulosclerosis and renal fibrosis in mice with DKD (284,285). The HDM KDM3A is recruited to
the CTGF promoter to activate transcription, augmenting
hyperglycemia-induced CTGF induction in RTECs (286). Additionally, histone
lysine-specific demethylase 1 aggravates renal fibrosis by
decreasing SIRT3 expression and activating the TGF-β1/Smad3 pathway
(Table III) (287).
Numerous inhibitors (such as tazemetostat, GSK126
and GSK-J4) of methyltransferases and demethylases are undergoing
clinical trials for cancer treatment (288,289). Such preclinical research
utilizing pharmacological drugs that target methylation may advance
DKD treatment.
During the progression of renal fibrosis, numerous
proteins undergo ubiquitination and deubiquitination (290). E3 ubiquitin ligase of the TRIM
subfamily of RING-containing proteins is notably associated with
renal fibrosis in DKD (195,291). TRIM18 promotes EMT,
inflammation and fibrosis in HK2 cells via ubiquitination of PTP1B
and activates STAT3 signaling (292). Upregulation of TRIM13
suppresses mesangial collagen synthesis in DKD by promoting
ubiquitination of C/EBP homologous protein, providing insight into
the application of histone ubiquitination in the management of DKD
(293). Smurf1/2, HECT-type E3
ubiquitin ligases, participate in renal fibrosis by ubiquitinating
TGR5 and ChREBP (294-296). Additionally, serum creatinine
enhances the interaction between c-Cbl and CKIP-1 by promoting the
phosphorylation of c-Cbl, thereby increasing c-Cbl-mediated
ubiquitination of CKIP-1 to downregulate its expression, which
exacerbates renal inflammatory fibrosis in diabetic mice (297). USP modulates EMT and the
production of ECM components by deubiquitinating and stabilizing
their respective substrates (22,298). For example, USP9X decreases
Nrf2 ubiquitination and deubiquitinates Cx43 to regulate the EMT
process (299-301). Ubiquitination and degradation
of KDM3A increases TGF-β-induced factor 1 transcriptional activity,
inactivating TGF-β1/Smad2/3 signaling and suppressing the
progression of DKD (302). TAK1
mediates the phosphorylation of Ski-related novel protein N (SnoN),
leading to SnoN ubiquitination and degradation, which enhances EMT
and ECM deposition to promote renal fibrosis during DKD (Table III) (303,304). Modulation of ubiquitination may
play a promising role in the treatment of DKD.
High glucose enhances the SUMOylation of STAT1,
which prevents STAT1 from exerting an effective protective function
in inhibiting EMT (305).
Furthermore, diabetic conditions activate TGF-β/Smad signaling via
SUMO2/3 mediated SUMOylation of Smad4 in MCs (306,307).
O-GlcNAc augments the protein stability,
transcriptional activity and nuclear translocation of ChREBP.
Diabetic conditions increase the levels of O-GlcNAcylated ChREBP,
which further lead to lipid accumulation and upregulation of
fibrotic proteins in MCs (308). In addition, O-GlcNAc is, in
part, coupled to the profibrotic MAPK signaling pathway via
inhibition of Akt phosphorylation and potentially through ROS
(309).
The hyperglycemia-induced increases in
phosphorylation and oxidation of mitochondrial proteins contributes
to tubular dysfunction during DKD (310). S-nitrosylation serves a role in
the precise regulation of glomerular homeostasis by modulating
multiple important signaling pathways in DKD models. Specifically,
S-nitrosylation of laminin prevents the development of glomerular
nodules, while denitrosylation of S-nitrosoglutathione reductase
and increased S-nitrosylation of β3-integrin collectively result in
diffuse glomerulosclerosis in podocytes (311,312).
An elevation in histone lactylation is observed in
mice with DKD. H3K14la promotes the transcription of KLF5 in RTECs
of DKD (313,314). Notably, disruption of the
lactate/H3K14la/KLF5 pathway mitigates renal dysfunction and DKD
pathology (313). In addition,
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a
key glycolytic enzyme, is associated with renal fibrosis and
dysfunction. Lactate generated from PFKFB3-mediated tubular
glycolytic reprogramming significantly enhances histone
lactylation, particularly H4K12la, which is enriched at the
promoters of NF-κB signaling genes (such as Ikbkb, Rela and Relb),
activating their transcription, and facilitating the inflammatory
response and renal fibrosis (39).
NaCr exerts an antidiabetic effect, decreases blood
glucose and serum lipid levels, and alleviates renal function and
DKD-associated inflammatory and fibrotic damage. NaCr induces
histone Kcr and H3K18 crotonylation. However, NaCr and
Cr-CoA-induced histone Kcr and renoprotective effects are abrogated
by inhibiting the activity of ACSS2 or histone acyltransferase p300
in vitro (241).
Moreover, ACSS2 notably increases H3K9cr levels in renal tissues
and tubular epithelial cells (48,91). Genetic and pharmacological
suppression of ACSS2 inhibits H3K9cr-mediated IL-1β expression,
which alleviates IL-1β-dependent macrophage activation and tubular
senescence to delay renal fibrosis (48). Targeting ACSS2 may serve as a
potential therapeutic intervention for the management of DKD, but
warrants further preclinical and clinical investigations.
Beyond its role in energy supply, BHB serves as a
bioactive molecule that exerts numerous protective effects,
including in DKD. BHB antagonizes glomerulosclerosis in diabetic
rats via upregulation of MMP2 production through elevation of
H3K9bhb at the MMP2 promoter (315). Moreover, BHB ameliorates
hyperglycemia-induced podocyte injury in vitro (316).
The interaction between PTMs of a protein to
modulate protein function through positive/negative regulatory
effects is termed PTM crosstalk. Positive crosstalk refers to
multiple PTMs that occur in the same local protein sequence area
(typically within a span of five amino acids) but do not happen in
the same residues, occurring concurrently or with a causal or
chronological connection (6).
Negative crosstalk is characterized by the direct competition of
two PTMs for the same residue in a causal or temporal manner.
Crosstalk between multiple PTMs is more frequently observed in key
protein domains such as histones and protein kinases in DKD. For
example, dysregulation of O-GlcNAcylation of β-actin Ser199 and
phosphorylation of β-actin Ser199 contributes to morphological
changes in DKD (317). Elevated
H2AK119-Ub and H2BK120 mono-ubiquitination (H2BK120-Ub) are
observed in diabetic rats (318). Histone H2AK119-Ub and
H2BK120-Ub promote diabetic renal fibrosis by upregulating the
expression of methyltransferases SET7/9 and SUV39H1, thereby
enhancing active H3K4Me2 and suppressive H3K9Me2 marks,
respectively (318). Zhang
et al (263) reported
that Dot1l and HDAC2 mutually inhibit their binding to the Edn1
promoter to regulate the production of Edn1, which is involved in
renal fibrosis in DKD. A novel ubiquitin-like modification,
neddylation, stabilizes RhoA by reducing its ubiquitination,
thereby activating the ERK1/2 pathway and driving interstitial
fibrosis (319). Moreover,
OTUD5 deubiquitinates K63-linked TAK1 at the K158 site, which
prevents the phosphorylation of TAK1 and decreases downstream
inflammatory responses in podocytes (230). Furthermore, different PTMs
jointly regulate DKD progression through combined or antagonistic
pathways, yet their cross-interaction networks need systematic
elucidation (Fig. 3).
PTMs modulate gene expression, and protein
stability and activity, serving a pivotal role in DKD progression
as a key event in the pathological timeline. Despite increasing
attention, the majority of PTMs in DKD are still in the preliminary
research stage, and their regulatory networks and cell
type-specific roles need further clarification (320,321). Notably, studies have identified
PTMs as potential biomarkers for DKD occurrence and development
(322-324). For example, plasma
2,6-sialylation of triantennary glycan A3E is associated with DKD
risk (322). Moreover, patients
with DKD exhibit abnormal lactate metabolism, and there is an
association between urinary lactate levels and renal tubular injury
(323,324). Overall, these findings
highlight the translational importance of PTMs in early diagnosis
and progression assessment of DKD. Accumulating evidence further
demonstrates the therapeutic prospects of targeting PTMs for DKD
treatment (320,325). Numerous drugs exert biological
effects partly by targeting PTM regulators. For example, metformin,
melatonin and resveratrol target SIRT1 to regulate autophagy,
oxidative stress, lipid deposition and renal fibrosis in DKD
(326-328). Additionally, sodium-glucose
cotransporter 2 and RAAS inhibitors exert renoprotective effects on
DKD by impacting O-GlcNAcylation (329).
At present, there are numerous small-molecule
inhibitors targeting PTMs used in the therapeutic research of DKD
models. Small-molecule inhibitors of HDACs (such as trichostatin A,
vorinostat and valproic acid targeting class I and II HDACs),
methyltransferases (such as GSK-J4 targeting KDM6A) and
phosphorylation-related enzymes (such as rapamycin targeting mTOR)
have exhibited favorable efficacy in preclinical models, as
evidenced by the mitigation of renal fibrosis and inflammation, and
improvement of renal function (320,330-332). Despite the encouraging results
of PTM activators or inhibitors in experimental models, their
clinical therapeutic efficacy is subject to limitations. The wide
presence of PTMs in vivo and the crosstalk among distinct
PTMs poses challenges to selective targeting, as targeting a single
modification may interfere with interrelated pathways and lead to
unexpected consequences. Moreover, individual enzymes typically act
on multiple substrates and signaling pathways, causing global
changes instead of gene- or organ-specific effects. At present,
clinical trials of inhibitors of methyltransferases and HDACs, such
as tazemetostat, chidamide and entinostat, are concentrated on
therapy for cancer, including various types of relapsed/refractory
lymphoma, prostate cancer and renal cell carcinoma (333-336). No specific PTM modulators have
been granted approval for clinical trials in DKD to date. The
safety and efficacy of PTM interventions in humans await rigorous
validation.
In summary, PTMs are key regulators that precisely
modulate protein function, stability, interactions and subcellular
localization. Their pervasive involvement in biological processes
provides insights into the pathogenesis of DKD. The evolving
research on PTM-regulatory agents, including novel compounds and
ongoing clinical trials, underscores their therapeutic promise.
However, current evidence for specific PTMs in DKD relies on
cross-sectional studies from preclinical models, with a notable
absence of systematic longitudinal research tracing the dynamic PTM
alterations throughout the course of DKD onset and progression.
Moreover, the intricate crosstalk among different PTM pathways
remains poorly elucidated.
To bridge these gaps and advance clinical
applications, future research should prioritize several key
directions. First, implementing single-cell and spatial multi-omics
technologies is essential to delineate PTM landscapes at cellular
and compartment-specific resolution in the kidney. Second, the
development of highly selective modulators, leveraging advanced
structural biology and proteolysis-targeting chimera technology,
will help to minimize off-target effects. Third, given the
interconnected signaling networks in DKD, investigating rational
combination strategies targeting multiple PTMs or integrating PTM
modulation with conventional therapy may enhance efficacy and
overcome resistance. Finally, translational efforts should
prioritize validating specific PTM signatures as non-invasive
biomarkers for early diagnosis and precise staging of DKD,
ultimately facilitating personalized therapeutic strategies.
Overall, a deeper understanding of PTM-driven
mechanisms, combined with innovative technology and translational
validation, is pivotal in transforming the landscape of DKD
diagnosis and treatment.
Not applicable.
YW and LY conceived the study. MH, ZM, YZ and RY
performed the literature review and constructed the figures and
tables. MH, ZW, LZ, LW and YW revised the manuscript. Data
authentication is not applicable. All authors have read and
approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by the National Science Funding
in China (grant nos. 82370823 and 82400952), the Tongzhou District
Science and Technology Project (grant nos. KJ2023SS011 and
JCQN2023001), the Non-communicable Chronic Diseases-National
Science and Technology Major Project (grant no. 2023ZD0508100).
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