Diabetic kidney disease (DKD), recognized as a
severe chronic microvascular complication of diabetes, has emerged
as the leading cause of chronic kidney disease, surpassing chronic
glomerulonephritis in incidence (1). Clinically, DKD is characterized by
progressive proteinuria, edema and hypertension. Pathologically, it
affects multiple renal structures, including glomeruli, tubules and
microvessels, ultimately culminating in end-stage renal disease
(2). DKD diagnosis is performed
through biopsy; however, the filtration rate and albumin excretion
rate enable initial identification (3). Notably, accumulating evidence has
underscored pre-biopsy biomarker screening as important for curbing
disease progression (4–6). Therefore, the identification of
important therapeutic targets and molecular biomarkers in
early-stage DKD holds notable clinical implications. Shifting away
from established DKD research models, the present review identified
endoplasmic reticulum (ER) stress (ERS) as a prospective
therapeutic focus, including a systematic dissection of its role in
disease progression and a thorough re-evaluation of herbal
treatment approaches.
The ER, a notable cellular organelle, orchestrates
polypeptide folding and protein processing, functions that underpin
its roles in calcium storage and regulation, lipid metabolism, and
glucose homeostasis (7). ERS can
be initiated by two distinct mechanisms: i) Endogenous factors such
as cancer and neurodegenerative diseases, which disrupt cellular
processes (8); and ii) exogenous
stressors such as microenvironmental alterations and chemical
insults that induce ERS responses (9). Microenvironmental perturbations and
diverse stressors, including metabolic dysregulation,
cancer-associated stress, drug toxicity and radiation, elicit the
unfolded protein response (UPR) in the ER, a hallmark of ERS
(10). ERS serves as one of the
fundamental mechanisms underlying metabolic dysfunction across
renal organs and tissues. As a trophic signaling hub in metabolic
disorders such as obesity and type 2 diabetes, the ER integrates
inflammation, autophagy and apoptosis pathways, while modulating
cytokine release (11). ERS
induces dynamic changes in the expression of inositol-requiring
enzyme 1α (IRE1α), PKR-like ER kinase (PERK), activating
transcription factor (ATF)6 and glucose-regulated protein
(GRP)78/binding immunoglobulin protein (BiP). Following energy
metabolism fluctuations, these metabolism sensors (IRE1α, PERK and
ATF6) dissociate from GRP78/BiP, triggering increased metabolic
activity and protective responses such as autophagy (10). Failure to restore homeostasis via
translational arrest and chaperone upregulation leads to the
initiation of CHOP-dependent apoptosis, a determinant of stressed
cell fate (2,12).
ERS-related protective responses activate three
stress protein pathways. First, starting with the IRE1α-spliced
X-box binding protein 1 (XBP1s) pathway, phosphorylated (p-)IRE1α
dimerization catalyzes XBP1 mRNA splicing, generating
nuclear-translocated XBP1 that activates ER-associated degradation
(ERAD) or promotes mRNA decay during adaptive UPR. Concurrently,
tumor necrosis factor receptor-associated factor 2 (TRAF2)-mediated
JNK activation contributes to dual-function UPR signaling,
balancing adaptive and apoptotic responses. Second, p-PERK
dimerization in the PERK/eukaryotic initiation factor 2 (eIF2)
pathway drives eIF2 phosphorylation, which enhances ATF4
translation to elicit adaptive UPR. During severe ERS, ATF4 induces
CHOP expression, activating the apoptotic arm of the UPR. Third, in
the ATF6 axis, chaperone dissociation of GRP78/BiP promotes Golgi
trafficking, where proteolytic processing generates ATF6 p50. This
nuclear effector drives the adaptive UPR via chaperone and foldase
transcription or the apoptotic UPR via ERAD activation (13).
Collectively, the IRE1α/XBP1s, PERK/eIF2 and ATF6
pathways balance ERS-induced survival and apoptosis through UPR
modulation: Moderate UPR restores homeostasis, while persistent ERS
activates apoptotic signals such as caspase-12, leading to cell
death (Fig. 1) (8–14).
Preclinical and clinical investigations have
consistently revealed ERS marker upregulation in renal tissues of
patients with DKD and relevant animal models (15–17).
Pathological changes in DKD tend to start early with thickening of
the basement membrane, gradually spreading to glomeruli,
microvessels and tubules. By contrast, changes in glomerular
hyaluronan appear in the late stages of DKD (18,19).
Persistent urinary protein abnormalities stem predominantly from
four sources: i) Renal filtration barrier defects, including those
affecting the basement membrane, podocytes and associated cells
(20); ii) damage across renal
tubular segments (21); iii) renal
interstitial functional impairment (22); and iv) immune cell population
dysregulation (23). In
conclusion, renal histopathology reveals that ERS impacts DKD in
three notable manners: Glomerular filtration membrane injury, renal
tubular reabsorptive dysfunction and renal interstitial remodeling
with immune cell dysregulation (24).
Studies in DKD model mice have revealed that ERS
contributes to glomerular injury, as demonstrated by increased
GRP78/caspase-12 expression and reduced Bcl-2 levels (25–27)
Notably, genetic deletion of ER protein 44 in db/db mice
upregulated ATF6, XBP1 and CHOP, further indicating ERS involvement
in glomerular filtration membrane injury (28). Composed of endothelial cells,
basement membrane and podocytes, the glomerular filtration membrane
is important for blood filtration. Damage to these components
drives early DKD progression and proteinuria (27). Surface-bound GRP78 drives
extracellular matrix (ECM) accumulation through PI3K/Akt
activation, while the AMP-activated protein kinase (AMPK)/mTOR
pathway promotes late-stage PERK/CHOP upregulation to enhance
autophagy, and the IRE1/NF-κB pathway mediates ERS-induced
inflammation in podocytes (29–31).
Compared with individuals without DKD, renal biopsy analyses of
patients with DKD have revealed increased GRP78 and caspase-12
expression in human glomerular podocytes (28,32).
The elevation of ATF6 and PERK in human podocytes triggers lipid
metabolism disorders and inflammation, which are suppressed by
JNK-mediated insulin activity (33). Mechanistically, the high
glucose-induced elevation of PERK, ATF6 and IRE1α in rat podocytes
is linked to protein arginine methyltransferase 1 (PRMT1) (34). Concurrently, the activation of
XBP1s in glomerular mesangial cells triggers histone-lysine
N-methyltransferase SETD7-mediated histone methylation, leading to
the upregulation of DKD-associated monocyte chemoattractant protein
1 (35,36). These findings indicate that ERS
influences the expression of UPR-induced transcription factors,
which in turn contribute to fibrotic and inflammatory pathological
changes, thereby regulating the balance between adaptive and
apoptotic states in podocytes.
The depletion of terminally differentiated
podocytes, which form the glomerular filtration barrier, is
characteristic of chronic kidney diseases, including DKD. Numerous
studies have revealed an association between ERS and podocyte
injury in DKD, as ERS markers are upregulated in human and murine
podocytes exposed to high glucose; this process is induced by the
dysregulation of hyperglycemia, lipid metabolism and insulin
signaling (37,38). In mouse podocytes, the accumulation
of advanced glycation end-products (AGEs) and high-glucose exposure
activate GRP78, CHOP and caspase-12 through distinct pathways,
ultimately driving podocyte apoptotic processes (39). PERK-eIF2α activation induces
CHOP-mediated podocyte apoptosis, and PERK phosphorylation triggers
a CHOP-reticulon 1A (RTN1A) positive feedback loop for synergistic
apoptotic enhancement (40).
Dysfunction in the insulin PI3K/Akt pathway may underlie
GRP78/CHOP-mediated ERS and podocyte apoptosis. Reduced activity of
PTEN, a downstream inhibitory regulator, exacerbates ERS, while
MEK/ERK signaling counteracts this pathological effect (41). The GRP78-mediated modulation of the
MEK kinase 1 (MEKK1)/JNK signaling cascade induces podocyte
apoptosis through MEKK1-dependent Ser280 phosphorylation (42).
The ERAD pathway is a specialized mechanism within
the ER that employs the ubiquitin-proteasome system to degrade
misfolded or aberrantly modified proteins, serving an important
role in eliminating these faulty proteins from cells (43). Derlin-2 expression is elevated in
podocytes from patients with DKD biopsies, triggering ERAD to
sustain the cellular balance (44,45).
Similarly, ERS serves an important role in balancing podocyte
survival and apoptosis through autophagy, given that compared with
DKD, podocytes inherently exhibit a higher basal autophagic
activity (46) High glucose levels
increase eIF2α, CHOP, caspase-3/12, GRP78, ATF6 and PERK levels in
podocytes through the inhibition of autophagy, whereas
sarcoendoplasmic reticulum calcium-ATPase (SERCA)2b-mediated ERS
attenuation is associated with AMPKα-induced autophagy (46,47).
The intercellular transmission of ERS signals, coupled with
podocyte-intraglomerular cell interactions, suppresses ERAD through
derlin-2 downregulation, inducing podocyte apoptosis in DKD
(48). Additional evidence has
shown that GRP78/CHOP activation in endothelial cells drives
epithelial-mesenchymal transition (EMT) (49), implying a potential role for
glomerular endothelial cells in DKD pathogenesis, although the
underlying mechanisms remain ambiguous.
UPR-activated transcription factors drive fibrosis
and inflammation in glomerular podocytes at the early stage of
diabetic kidney injury. Three ERS pathways collectively influence
disease progression, including: i) Regulation of podocyte apoptosis
through the PI3K/Akt, PTEN and MEK/ERK signaling pathways; ii)
maintenance of cellular homeostasis through the activation of ERAD;
and iii) modulation of podocyte autophagy via AMPK (50,51).
In addition, key ERS factors also contribute to the DKD process by
affecting intraglomerular mesangial cells and podocytes (52).
Composed of Henle's loop, proximal and distal
tubules and collecting ducts, renal tubules reabsorb small
molecules and lipids, with their epithelium serving as a key
DKD-targeted cell type susceptible to injury (53,54).
Extensive research has established that ERS contributes to
DKD-related renal tubular injury, as evidenced by the upregulation
of differential ERS markers in human biopsies, animal tissues and
in vitro models (15,55–57).
This process is driven by the AGE/receptor for AGEs (RAGE) axis,
PRMT1 and histone H4 deacetylation (15,58,59),
while it is alleviated by calbindin-D28k, transmembrane BAX
inhibitor motif-containing protein 6, sestrin 2 and dapagliflozin
(60,61). Renal tubular ERS markers (notably
including GRP78) can modulate the autophagic processes and drive
inflammatory responses by regulating mitochondrial function and
reactive oxygen species (ROS) generation (62,63).
Saturated fatty acid-associated factors, such as
carbohydrate-responsive element-binding protein, cholesterol and
palmitic acid (PA), promote ERS marker upregulation in renal
tubular cells, causing lipid accumulation and apoptotic cell death
(64,65). Therefore, the comprehensive role of
ERS in renal tubules is closely intertwined with autophagy,
inflammation and lipid peroxidation.
In the renal tubular system, the proximal tubule
reabsorbs glucose, amino acids, HCO3−,
Cl− and Na+, while secreting H+.
By contrast, the distal tubule and collecting ducts mainly mediate
Na+ and water reabsorption alongside K+
secretion. The proximal and distal tubule of the kidney functional
distinction partially explain the structural variations in ERS
signaling, with GRP78-governed ATF4/p16/p21 axes promoting
AGE/RAGE-driven premature cellular senescence in mouse proximal
tubular cells (66). GRP78 and
protein disulfide isomerase exhibit distinct regulatory dynamics
between proximal and distal tubules, varying across early and late
stages of diabetes-induced ERS. Early-stage diabetes triggers PERK
activation, while late-stage disease promotes ATF6 activation in
renal tubules, resulting in stage-dependent differential ERS
responses between proximal and distal segments in DKD (67).
ERS notably regulates renal cell function by
suppressing inflammation, inhibiting abnormal proliferation and
fibrosis, and combating oxidative damage through the precise
modulation of DKD pathways, including the PERK/CHOP and caspase-12
pathways (53,68,69).
The mechanistic exploration of ERS in DKD pathway regulation sheds
light on DKD pathogenesis and facilitates the identification of
novel therapeutic targets (Fig.
2).
The PERK/CHOP pathway regulates ERS and contributes
to DKD. The core aspects of the PERK/CHOP pathway comprise the
following mechanisms: Initially, ERS is triggered when high glucose
levels, oxidative stress and inflammation lead to misfolded protein
accumulation in the ER, prompting GRP78/BiP dissociation from PERK
and subsequent kinase activation (70). Subsequently, the PERK/eIF2α/ATF4
axis is activated; PERK phosphorylates eIF2α, globally inhibiting
translation to reduce ERS burden. Simultaneously, p-eIF2α
selectively promotes ATF4 translation, leading to CHOP expression
(71) Finally, CHOP-mediated
apoptotic signaling occurs (72)
CHOP, a transcription factor, upregulates pro-apoptotic genes, such
as Bcl-2-interacting mediator of cell death (Bim), p53 upregulated
modulator of apoptosis and Bax, and downregulates Bcl-2, ultimately
inducing apoptosis (73).
The PERK/CHOP pathway mediates DKD podocyte injury
through high glucose-activated PERK/eIF2α/ATF4/CHOP signaling,
inducing apoptosis, foot process effacement, proteinuria and
glomerulosclerosis, which are exacerbated by pathway
hyperactivation (74). The
PERK/CHOP pathway drives mesangial cell proliferation, fibrosis and
ECM deposition, mediated via pathways such as the TGF-β1/connective
tissue growth factor pathway, in DKD, additionally serving as a
central mediator of proteinuria and glomerulosclerosis (75). In DKD, the CHOP pathway mediates
renal tubular injury. High glucose-induced ERS promotes tubular
apoptosis through the PERK/CHOP axis and activates pro-inflammatory
cytokines such as IL-6 and TNF-α to exacerbate renal interstitial
inflammation (68). Renal
tubulointerstitial fibrosis is an important step in the progression
of DKD to end-stage renal disease. Sustained PERK activation
enhances ATF4 transcription to upregulate CHOP, which downregulates
Bcl-2 and promotes apoptosis through ROS production and ATP
depletion (76). Concurrently,
CHOP triggers growth arrest and DNA-damage-inducible 34 activation
to facilitate eIF2α dephosphorylation, a negative feedback
mechanism that restores transiently-arrested protein synthesis in
the PERK pathway (77).
The PERK/CHOP regulatory axis balances adaptive and
apoptotic responses to ERS through integrated positive and negative
feedback mechanisms (78). PERK
and its downstream effector CHOP exhibit segment-specific
regulation across different regions of the renal tubule. Renal
tubular cells secrete CHOP-induced fibronectin, driving mesenchymal
fibrosis in DKD, a process implying that PERK/CHOP signaling
controls the synthesis and release of ECM proteins in these cells
(79). The RTN1A/PERK/CHOP
positive feedback loop exacerbates ERS-induced podocyte apoptosis,
highlighting the dual role of the PERK/CHOP pathway in maintaining
ERS balance and promoting pathological cell death (80).
Caspase-12 acts as a key executor of apoptotic
signaling, with its activation closely linked to ERS-induced cell
death (81). Upon ER misfolded
protein accumulation, for example, due to high blood glucose
levels, oxidative stress or calcium dyshomeostasis, GRP78/BiP
dissociates from ER membrane sensors such as PERK, IRE1 and ATF6 to
bind misfolded proteins, triggering the activation of caspase-12 as
a downstream responder to ERS signals (82,83).
In non-stressed cells, GRP78 associates with pro-caspase-12 to
suppress its activity. During ERS, GRP78 dissociation exposes the
active site for proteolytic processing by upstream enzymes,
including IRE1α and calpain, generating active caspase-12 (p35/p12
subunits) that cleaves caspase-3 to initiate apoptosis (84,85).
In patients with DKD, high glucose induces ERS,
which activates caspase-12 and promotes the apoptosis of podocytes
and tubular epithelial cells, accelerating proteinuria and renal
interstitial fibrosis (86). In
the DKD mouse model, CHOP overexpression upregulates caspase-12 to
promote apoptosis, whereas caspase-12 inhibition attenuates high
glucose-induced renal cell injury (87). ERS also induces calcium
dyshomeostasis and mitochondrial calcium overload, indirectly
activating the mitochondrial apoptotic pathway via the
ER-mitochondrial axis (88).
ER-released Ca2+ activates peripheral calpains,
prompting their translocation to the cytoplasm. Calpain activation
results in translocation to the ER outer membrane, triggering
caspase-7 translocation and activation (87,89).
Both factors process pro-caspase-12 into an active form that
translocates to the cytoplasm, activates caspase-9 and −3 through
the cytochrome c (CytC)-independent pathway and induces
apoptosis (90). In addition, the
IRE1α-TRAF2 complex activates caspase-12 through calmodulin
decarboxylase, thereby initiating the caspase-mediated apoptotic
pathway (91).
Caspase-12-dependent signaling contributes to severe podocyte and
tubular cell injury in DKD. Therapeutic targeting of this pathway
mitigates ERS-mediated apoptosis, slowing DKD progression (92,93).
Therefore, caspase-12 signaling is important for ERS-induced
apoptosis. Despite genetic polymorphisms limiting its activity in
humans, caspase-12 retains diagnostic and therapeutic value for ERS
(94). Targeting the caspase-12
pathway may provide novel targets for the treatment of DKD.
JNK, originally identified in its capacity to
phosphorylate the amino terminus of the transcription factor c-Jun
(95), is also referred to as
stress-activated protein kinase. Extracellular stimuli, such as
stress signals, cytokines and growth factors, activate JNK, with
the activation relying on the cellular microenvironment. JNK
inhibition reduces podocyte apoptosis and matrix deposition, and
combination with PERK/CHOP inhibitors may enhance therapeutic
efficacy (96,97). As an important branch of the MAPK
cascade, the JNK pathway orchestrates multiple physiological
processes (98). During ERS,
activated IRE1α engages TRAF2 to trigger apoptosis
signal-regulating kinase 1 (ASK1) activation, generating a trimeric
complex that sequentially activates JNK, CHOP and pro-apoptotic
factors such as BH3-interacting domain death agonist and Bim, a
process that suppresses anti-apoptotic genes, including Bcl-2 and
Bcl-xL, and initiates mitochondrial apoptotic pathways (99–102). In addition, phosphorylation at
the MEKK1 Ser280 residue activates the JNK signaling pathway,
thereby promoting ERS-induced podocyte apoptosis (38,103). High glucose triggers JNK
activation in renal cells, inducing apoptosis and fibrosis. These
processes are alleviated by JNK inhibitors, which reduce
CHOP/caspase-3-dependent apoptosis in ERS-impaired podocytes to
mitigate DKD-related renal injury (33). Acting as a central stress response
hub, the JNK pathway integrates external stimuli with intracellular
signaling to govern inflammation and disease progression, with
functional complexity emerging from stimulus subtype specificity,
stimulus intensity and cellular context (104,105). Despite the challenges of drug
development targeting JNK (such as poor specificity and high
concentrations required to inhibit c-Jun phosphorylation), its
potential applications in areas such as DKD and neurodegenerative
diseases make it a promising therapeutic target (106–109).
The PERK/eIF2α signaling axis, a key branch of ERS
signaling, maintains intracellular proteostasis by regulating
protein synthesis and gene expression (110). Following the accumulation of
misfolded or unfolded proteins in the ER, this pathway is activated
to promote either stress adaptation or apoptosis through global
translation inhibition and induction of stress-responsive genes
(111). The key component of this
pathway, PERK, is an ER transmembrane protein with a kinase domain
on the cytoplasmic side, while only its stress-sensing domain is
present within the lumen of the ER) (112). In unstressed cells, PERK stays
inactive by associating with the ER chaperone BiP that has
dissociated from GRP78 (113). By
contrast, eIF2α is a key factor in the initiation of protein
translation, and phosphorylation at its Ser51 site is a central
event in the activation of the PERK/eIF2α pathway. This pathway
coordinates cellular homeostasis through multifaceted mechanisms,
such as translation repression for energy conservation, amino acid
transporter induction for survival and proteostasis regulation
through reduced synthesis, enhanced folding through mechanisms such
as BiP upregulation, or misfolded protein degradation, for example,
via ERAD (72).
The PERK/eIF2α branch of the UPR signaling pathway
induces autophagy-associated gene expression through the
transcriptional regulation of ATF4, thereby promoting the
transcription of autophagy-associated genes (114). Downstream genetic effectors
include beclin-1, which mediates autophagosome biogenesis and
maturation, the ubiquitin-like system and transport receptor genes
such as p62 and next to BRCA1 gene 1 protein (115). These transport receptor genes
undergo selective degradation via ubiquitinated cargoes. Vaspin, a
serine protease inhibitor, suppresses p62 aggregation by forming
complexes with GRP78 and heat shock 70 kDa protein 1L (116,117). This mechanism protects organelles
from metabolic stress-induced damage through endocytosis-driven
autophagy facilitation, maintaining cellular homeostasis under
stress (118). The PERK/eIF2α
pathway is a ‘regulatory hub’ for ERS through precise regulation at
the translational level and reprogramming of gene expression to
maintain a balance between cell adaptation and death (119).
The IRE1 signaling cascade acts as a core ERS
effector, governing adaptive or apoptotic cell fates predominantly
by modulating mRNA splicing and gene transcription (120,121). The pathway is highly
evolutionarily conserved from yeast to mammals and is a key
mechanism for maintaining ER protein homeostasis. The IRE1/XBP1
axis preserves cellular homeostasis during acute stress by boosting
protein folding, degradation and transport, while governing the
activity of secretory cells, such as plasma and pancreatic β-cells,
for efficient antibody and insulin production (122,123). Conversely, chronic ERS in
pancreatic β-cells engages the IRE1/JNK pathway, causing β-cell
death and diminishing insulin release (124,125).
The IRE1 pathway engages in crosstalk with the other
two UPR arms: The PERK/eIF2α and ATF6 pathways. The PERK branch
suppresses global translation through eIF2α phosphorylation to
reduce protein synthesis load, while ATF6 activates BiP, ERAD and
other chaperone genes through nuclear translocation (126,127). The IRE1 pathway promotes protein
folding and degradation through XBP1 splicing, concurrently
regulating cell fate through JNK activation and the regulated
IRE1-dependent decay (RIDD) pathway (111,128). Collectively, these three pathways
dictate cellular outcomes during stress, promoting survival under
acute stress conditions and triggering apoptosis under prolonged or
severe stress (129). In the ERS
state, IRE1/XBP1 signaling directly promotes the expression of
Bcl-2, increases the binding of Bcl-2 to beclin-1 and downregulates
the activity of beclin-1, thus inhibiting autophagy (2). During early ERS, IRE1α assembles with
TRAF2 and ASK1 to activate the downstream JNK signaling cascade,
which phosphorylates Bcl-2 to promote its dissociation from
beclin-1 and encourages subsequent autophagy initiation (92,93).
In addition, XBP1, a downstream effector of IRE1α, promotes
autophagy through beclin-1 activation (43). Blocking the kinase and RNase
activities of IRE1α has been shown to intensify PA-induced
cytotoxicity in renal tubular cells, indicating that IRE1α protects
against PA-mediated kidney injury in DKD (130). The IRE1 signaling pathway is a
‘multifunctional hub’ of the ERS response, responsible for shutting
down and splicing of the mRNA that encodes secretory proteins in a
process called regulated RIDD to decrease ER protein load and
spliced mRNA of XBP1 that activated the transcription of ER
hemostatic factors as chaperone and endoplasmic
reticulum-associated degradation components that degraded unfolded
and misfolded proteins in an attempt to resolve endoplasmic
reticulum stress; if this stress was unresolved, XBP1 upregulated
the expression of JNK that activated podocytes, tubular apoptosis,
and inflammation (131), and its
aberrant activation is closely associated with a variety of
diseases(such as Sepsis, DKD, breast cancer et.) (131–133).
Calcium channels are the core molecular machinery
regulating the intracellular flow of Ca2+ across the
membrane (129). DKD marked by
glomerular mesangial matrix dilation, basement membrane thickening,
tubulointerstitial fibrosis and renal unit loss involves
Ca2+ as a key signaling molecule; calcium homeostatic
imbalance markedly drives disease pathogenesis (134,135). The ER functions as a primary
intracellular Ca2+ store, regulating calcium homeostasis
(136). During stress,
Ca2+ influx sustains cellular homeostasis by activating
the MAPK pathway, thereby promoting intracellular protein folding
(137,138). Excessive release of
Ca2+ into the cytoplasm initiates ERS, thereby
activating caspase-12-dependent autophagy (139). The transient ER surface calcium
concentration is a key signal that determines the activation of ER
autophagy (140). In addition,
ATP and other Ca2+ mobilizers antagonize mTOR-mediated
autophagy inhibition via Ca2+-dependent pathways,
thereby promoting beclin-1- or autophagy-related gene 7-dependent
autophagosome biogenesis (141,142). In addition, Ca2+ can
activate both protein kinase C (PKC) and death-associated protein
kinase (DAPK). PKC induces autophagy through an mTOR-independent
pathway, whereas DAPK promotes beclin-1 phosphorylation and
disrupts the beclin-1/Bcl-2 complex, thereby activating autophagy
(143,144). The ERS-associated inhibition of
PERK and IRE1 protects against kidney injury, mitochondrial
dysfunction and renal cell apoptosis by maintaining Ca2+
homeostasis, which blocks cytosolic release of CytC and
apoptosis-inducing factor, inhibits caspase-9 activation and
restores mitochondrial membrane integrity, thereby suppressing
pathological cell death pathways (145). Calcium channels are ‘signaling
hubs’ for cellular functions, and their diversity and sophisticated
regulatory mechanisms serve key roles in physiological and
pathological processes (129,134).
Research on AS modulation of DKD through ERS
intervention has primarily focused on DKD rodent models and
meta-analyses (26,47,150–152). In DKD rat models (47,150) induced by a high-fat diet combined
with streptozotocin (STZ), intragastric administration of AS-IV
effectively mitigated apoptosis in renal tubular epithelial cells.
This protective effect involved two primary mechanisms: i)
Downregulation of ERS-associated proteins, including p-PERK, ATF4
and CHOP; and ii) restoration of the homeostatic balance between
the pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2
(47,150). In STZ-induced DKD rats (26,151,152), AS-IV alleviated ERS-driven
podocyte apoptosis through three coordinated pathways: i)
Suppression of the PERK/ATF4/CHOP signaling cascade; ii) inhibition
of oxysterol-binding protein-related protein 150 (ORP150) and GRP78
expression; and iii) reduction of phosphorylation levels of PERK,
eIF2α and JNK (26,151). Similarly, in db/db mice and
podocytes exposed to high glucose or PA, two important pathological
stimuli in DKD, AS-IV mitigated ERS and reduced podocyte apoptosis
by restoring SERCA2 expression and activity (152). Collectively, AS-IV exerted
anti-ERS effects through a multi-targeted strategy: Blocking three
important ERS signaling pathways, including the PERK/ATF4/CHOP,
PERK/eIF2α and IRE1/JNK pathways, increasing SERCA2 expression and
decreasing ORP150 and GRP78 expression (Table I) (26,151,152).
Huangkui is a TCM approved by the Chinese National
FDA for nephritis treatment. Its therapeutic effect on DKD is
primarily mediated by active ingredients, particularly flavonoid
derivatives such as quercetin glycosides and kaempferol glycosides.
These components intervene in the core pathological mechanisms of
DKD, including ERS, oxidative stress, the inflammatory response,
apoptosis and renal interstitial fibrosis, thereby forming a
multi-dimensional protective network (159–164). Huangkui (158,159) can restore ER protein homeostasis:
The upregulation of molecular chaperone proteins GRP78 and GRP94
promotes correct protein folding, enhances ERAD of misfolded
proteins, and attenuates ER loading (165).
In summary, Huangkui capsules exert protective
effects against both glomerular and tubular injuries by regulating
multiple mechanisms, including signal transduction pathways,
nuclear receptor activities, inflammatory responses, mitochondrial
function and gut microbiota, thus providing novel drugs and
approaches for the treatment of kidney disease. Ge et al
(33) demonstrated that Huangkui
ameliorated renal damage by attenuating ERS in DKD model rats.
Through its multi-targeted mechanism, encompassing ERS inhibition,
and antioxidant, anti-inflammatory, antifibrotic and
podocyte-protective effects, Huangkui mediates multi-level
regulatory effects in DKD progression, with notable promise in
proteinuria control and delaying renal interstitial fibrosis
(33,171,172). The natural medicinal properties
of Huangkui provide a novel strategy for early intervention in DKD,
and the combination of Chinese and Western medicine, which is
particularly suitable for the long-term management of patients with
mild to moderate proteinuria (170)
OA, as a monounsaturated fatty acid, serves an
important role in the development of DKD, and its involvement in
kidney injury through the regulation of ERS has attracted
increasing attention. OA is naturally found in fruits and
vegetables. Podocytes, early DKD targets, exhibit dose-dependent OA
responses: Low-dose OA mitigates injury, while high-dose OA
triggers ERS-PERK-mediated apoptosis, impairing podocyte protein
synthesis and filtration barrier integrity. Mechanistically, CHOP
upregulation inhibits Bcl-2, activating mitochondrial apoptotic
cascades, such as the caspase-3-mediated cascade (173,174). OA also exerts context-dependent
effects on tubular fibrosis: Low ERS inhibits fibrosis, while
OA-induced ERS activates ATF6/CHOP to upregulate TGF-β1/α-smooth
muscle actin (α-SMA), driving EMT (175). Excessive OA drives mesangial cell
proliferation and ECM accumulation through ERS-hyperactivated mTOR
signaling, contributing to glomerulosclerosis (176). This underscores OA concentration
modulation as a promising DKD therapeutic strategy.
In preclinical models, OlA exhibits antioxidant,
antiglycation, anti-inflammatory and bactericidal activity, notably
ameliorating DKD by reducing ERS. In diabetic rats, OlA treatment
enhances the renal protein expression of p-AMPK/AMPK and peroxisome
proliferator-activated receptor γ coactivator 1-α (PGC-1α), while
concurrently decreasing the expression of CD68, collagen-IV, TLR4,
NF-κB and TGF-β1 (177). By
regulating lipid metabolism and inflammation through the
AMPK/PGC-1α and TLR4/NF-κB pathways, OlA mitigates renal injury in
diabetic rats. In DKD model mice, OlA administration notably
reduces the ALB-creatinine ratio (ACR). The marked DKD-induced
elevation in ERS markers, such as p-PERK, p-eIF2α, ATF-6, BiP and
CHOP, was notably decreased following OlA treatment, accompanied by
marked reductions in ROS and nuclear factor erythroid 2-related
factor 2 levels in glomerular mesangial cells (177,178). Furthermore, OlA administration
reduces TGF-β/Smad2/3 signaling and α-SMA expression, repairs renal
damage, alleviates albuminuria and suppresses diabetes-induced
renal fibrosis by inhibiting ERS and apoptosis (179). In combination with
N-acetylcysteine, OlA further attenuates oxidative stress and
reduces the ERS-induced activation of TGF-β/Smad2/3 signaling
(180).
Quercetin, a widely distributed natural polyphenol,
exhibits potent antioxidant, anti-inflammatory and multi-target
regulatory effects, making it a focal point of interdisciplinary
research in disease prevention (181,182). Quercetin exhibits efficacy in
treating metabolic diseases, including diabetes and its
complications. Quercetin enhances cell-mediated immunity by
upregulating IFN-γ secretion from Th1 lymphocytes and reduces
inflammation by downregulating IL-4 secretion from Th2 lymphocytes
(183). The protective effects of
quercetin are mediated through multiple mechanisms, including
inhibition of ROS production and mitochondrial permeability
transition-pore opening, suppression of lipid peroxidation,
elevation of glutathione and superoxide dismutase levels (184), inhibition of NF-κB, TNF-α and
IL-6 signaling (185), reduction
of inflammatory mediator release, suppression of
angiotensin-converting enzyme and NF-κB activity, and enhancement
of endothelial-dependent vasodilation (184,185). These actions collectively
regulate blood pressure and reduce urinary protein excretion.
Quercetin may improve glucose homeostasis by
modulating the expression of the microRNA-29 family, thereby
increasing glucose transporters and insulin-like growth factor 1
gene expression, ultimately mitigating diabetic complications
(186). In STZ-induced diabetic
male Wistar rats, quercetin exhibited hypoglycemic effects,
restored pancreatic morphology and β-cell function, reduced ERS
markers such as CHOP and endothelin-1, inhibited lipid
peroxidation, and enhanced antioxidant enzyme activities (183,187). Consequently, it lowered blood
glucose levels, protected pancreatic tissues, alleviated ERS and
improved oxidative status. Quercetin also inhibits platelet
aggregation, hypertension and lipid peroxidation (188). In metabolic disorders, quercetin
ameliorates diabetic endothelial dysfunction by targeting ERS,
highlighting its role in metabolic-endothelial crosstalk (189).
As metabolic disease therapy, the renin-angiotensin
system (RAS) inhibitors aliskiren (193,194) and valsartan (195,196) reduce DKD proteinuria by lowering
glomerular pressure, with evidence showing that ERS pathway
regulation contributes to their renoprotective effects in
RAS-driven DKD.
ACEIs and ARBs such as aliskiren and valsartan
inhibit renal ERS in DKD, and dual therapy yields cumulative
renoprotective effects via synergistic RAS blockade and ERS control
(193). Valsartan is recommended
by several guidelines, including the Kidney Disease: Improving
Global Outcomes (KDIGO) guidelines (197), as the preferred ARB for DKD with
hypertension, and its nephroprotective effect is partly attributed
to ERS modulation. The clinical use of aliskiren is currently
limited due to early clinical trials, such as the ALTITUDE study
(72,198), showing an increased risk of
hyperkalemia and renal injury when used in combination with an ARB,
but its single-agent modulation of ERS remains worth studying
(199–201). Aliskiren and valsartan exert
anti-apoptotic, anti-inflammatory and anti-fibrotic effects in DKD
by inhibiting RAS overactivation and modulating upstream or
downstream ERS. Valsartan, as a classical ARB, has been clinically
validated as an ERS regulator, particularly in the context of DKD
treatment. However, the ERS-targeting effect of aliskiren (a direct
renin inhibitor) remains to be further evaluated and balanced in
terms of its efficacy and safety (193). Basic research has confirmed that
angiotensin II exacerbates ERS in renal tubular epithelial cells by
activating the PERK/eIF2α/CHOP pathway, while ACEIs and ARBs
downregulate stress markers such as GRP78 and CHOP in renal tissue
(196,202). However, clinical studies have yet
to incorporate assessments of ERS-related biomarkers, thus direct
clinical evidence of ACEI and ARB exerting effects via inhibition
of ERS is lacking (193,196). The 2024 KDIGO guidelines
recommend RAS inhibitors for patients with DKD with proteinuria,
emphasizing blood pressure and proteinuria management but omitting
the discussion of ERS-related mechanisms (202).
CB1R, a notable cannabinoid receptor, is widely
distributed in renal vascular endothelial, mesangial, tubular and
immune cells (203,204). In DKD, hyperglycemia, oxidative
stress and inflammation activate CB1R, inducing renal inflammation,
fibrosis and metabolic dysfunction, including insulin resistance
(205–207). CB1R antagonists, such as
rimonabant and AM251, have been shown to improve glucose-lipid
metabolism in metabolic disorders through the blockade of CB1R
signaling, and their protective mechanism against DKD has been
demonstrated to be closely associated with modulation of the ERS
pathway (208,209). The protective effect of CB1R
inhibition in DKD is linked to ERS pathway modulation, with CB1R,
abundantly expressed in diabetic rats kidneys, mediating ERS and
apoptosis in rat mesangial Cells) under high glucose. CB1R
regulates palmitic acid-induced apoptosis in human renal proximal
tubular cells through the ERS pathway (210,211). CB1R antagonists are not
recommended in DKD guidelines; rimonabant has been withdrawn
globally due to severe psychiatric side effects such as depression
and anxiety (212). Subsequent
candidate CB1R antagonists, such as AM6545, remain in preclinical
research for DKD and have not yet been incorporated into guidelines
(213,214).
Endogenous cannabinoids activating CB1R may serve a
notable role in the pathogenesis of diabetic cardiomyopathy by
promoting MAPK activation, type-1 angiotensin II receptor
expression and signaling, AGE accumulation, oxidative and
nitrosative stress, inflammation, and fibrosis (215,216). Conversely, CB1R antagonists exert
anti-diabetic effects by increasing pancreatic β-cell glucokinase
and glucose transporter (GLUT)-2 expression, improving β-cell
insulin signaling and proliferation (for example, mitigating β-cell
loss in male Zucker diabetic obese rats, independent of weight
loss) (216,217). CB1R antagonists also upregulate
skeletal muscle GLUT-4 to ameliorate intermittent hypoxia-induced
insulin resistance, whereas CB1R agonists interfere with insulin
signaling pathways (218,219). CB1R antagonists modulate the ERS
pathway by blocking high-glucose- or inflammation-induced CB1R
signaling on several levels: i) Inhibiting oxidative stress and
calcium disruption (211); and
ii) attenuating inflammation and fibrosis, thereby improving renal
cell survival and renal function (220). The use of CB1R antagonists is
subject to notable limitations. Currently, to the best of our
knowledge, no human studies using CB1R antagonists have been
conducted, and the risk of psychiatric side effects remains to be
assessed (221,222). Consequently, clinical advancement
cannot proceed at this stage (223). However, it holds potential and
may provide a basis for DKD treatment following future animal
studies and clinical trials.
Chemical chaperones, such as TUDCA and 4-PBA, are
small molecules responsible for stabilizing protein conformation,
enhancing ER folding and promoting mutant protein transport. TUDCA,
a secondary bile acid, exhibits beneficial effects in various
disorders, including diabetes, obesity and neurodegenerative
disease (224). The
cytoprotective mechanisms of chemical chaperones primarily involve
the alleviation of ERS. 4-PBA, a small-molecule chaperone employed
in urea-cycle disorders, mitigates ERS to normalize hyperglycemia
and insulin resistance (225–227). Preclinical study has demonstrated
the efficacy of 4-PBA in preventing podocyte apoptosis in type 2
diabetes (228). In addition,
three widely used ERS inducers, clindamycin, dithiothreitol and
carbobenzoxy-Leu-Leu-leucinal, have been applied to assess ERS in
animal models and cell lines. 4-PBA was shown to alleviate
drug-induced ERS (229), while
drugs targeting PERK, IRE1α, eIF2α and ATF4, such as GSK2606414,
MKC-3946, salubrinal and trazodone, offer promise for ERS-related
disorder management (230,231).
In rats fed a high-salt diet, damage to the glomeruli and proximal
tubules was exacerbated, accompanied by increased urinary protein
excretion. Following treatment with TUDCA, the levels of proximal
tubular giant cells increased and urinary protein levels were
markedly decreased (232). TUDCA
and 4-PBA are not formally included in clinical guidelines for DKD.
However, the Chinese Guidelines for the Prevention and Treatment of
Diabetic Kidney Disease (2021 Edition) mention in the section on
‘Novel Therapeutic Targets for DKD’ that ‘chemical companions may
improve renal injury by alleviating ERS’, listing TUDCA as a
potential candidate drug (233).
Sodium-glucose co-transporter 2 (SGLT2) inhibitors,
such as empagliflozin and dapagliflozin, currently represent
first-line therapies for DKD. Their regulation of ERS involves
indirect multi-pathway interventions, and the direct association
between their renal protective effects and ERS inhibition requires
validation through mechanistic clinical trials (244,245). The 2024 KDIGO guidelines classify
SGLT2 inhibitors as a first-line therapy with Class 1A
recommendation for patients with DKD with an estimated glomerular
filtration rate (eGFR) ≥20 ml/min/1.73 m2, emphasizing
their role in delaying renal progression (246,247). However, ERS-related mechanisms
are not addressed. Existing large-scale clinical trials have
primarily focused on definitive renal endpoints, such as eGFR
decline and end-stage kidney disease, without systematic assessment
of ERS biomarkers (202,248–251). Thus, attention to ERS treatment
is warranted for kidney disease.
The aforementioned drugs exhibit pleiotropic
effects, indicating their lack of specificity for ERS inhibition;
thus, development of ERS-targeted therapeutics is warranted.
Notably, ERS exhibits dual effects: Moderate ERS restores
intracellular homeostasis, while sustained ERS drives renal damage
in DKD, meaning that human-targeted ERS research is warranted
(252–254). A deeper understanding of the
mechanisms underlying this process will help improve the treatment
of DKD.
As a major microvascular complication of diabetes
mellitus, DKD is closely associated with aberrant activation of
ERS. Factors such as hyperglycemia and oxidative stress trigger an
imbalance of protein folding in renal podocytes, tubular epithelial
and renal capsule cells, which activates the three core pathways of
the UPR, namely the IRE1α/XBP1, PERK/eIF2α/ATF4 and ATF6 pathways
(50,255). Short-term ERS maintains cellular
homeostasis by promoting protein folding and degradation, whereas
sustained overactivation induces pro-apoptotic factor expression,
such as CHOP expression, exacerbating inflammatory responses
through NF-κB pathway activation and mesangial fibrosis via
TGF-β1/Smad3 pathway dysregulation, which ultimately leads to
glomerulosclerosis and renal failure. Several stimuli disrupting
cellular homeostatic function induce ERS (58,256) (Fig.
1). The present review discusses ERS-related experimental
agents, preclinical models and clinical data, alongside an analysis
of the three UPR pathways in DKD renal histopathology.
Phase I and II clinical trials are underway for
ERS-modulating compounds such as alginate and TUDCA (257). Pharmacological interventions
against ERS have focused on blocking the excessive stress response.
However, although the aforementioned RAS inhibitors, SGLT2
inhibitors, 4-PBA and CB1R antagonists may regulate ERS through
indirect pathways, existing guidelines do not provide specific
recommendations based on this mechanism (258–260). Clinical trials lack ERS-related
endpoint data, and the causal relationship between medications for
the treatment of DKD, ERS) requires further validation through
targeted research. Western drugs, such as PERK inhibitors, IRE1α
endonuclease inhibitors and CHOP antagonists, have demonstrated
potential in attenuating apoptosis and fibrosis in animal models
(203,261–263); however, challenges associated
with target specificity and long-term safety remain.
ERS inhibitors commonly used in laboratory studies,
such as the chemical chaperone 4-PBA or the pathway-specific PERK
inhibitor GSK2606414, generally exhibit good tolerability in rodent
DKD models (264,265), but their clinical safety
assessments present significant challenges. Primarily, ERS is a
fundamental physiological mechanism enabling cellular responses to
abnormal protein folding, which is important in metabolically
active tissues such as pancreatic β-cells and hepatocytes. While
4-PBA alleviates ERS in renal tissues of rat models (266–268), its prolonged clinical application
may cause hyperammonemia and gastrointestinal mucosal irritation.
Furthermore, suppressing ERS responses in pancreatic β-cells can
impair insulin synthesis, potentially exacerbating glycemic
dysregulation (225). Secondly,
the risk of kidney-specific toxicity may be underestimated. Animal
models commonly involve young, healthy rats, whereas clinical
patients with DKD typically present with comorbidities such as
hypertension, cardiovascular disease and renal insufficiency,
markedly reducing drug metabolism capacity. In addition, drug
interactions remain unclear: Patients with DKD frequently require
concomitant hypoglycemic, antihypertensive and lipid-lowering
medications (269,270). Furthermore, ERS inhibitors may
compete with SGLT2 inhibitors for renal tubular excretion pathways
or affect the renal metabolism of ACEIs, increasing the risk of
adverse reactions such as hyperkalemia (271). Such interactions are challenging
to detect in controlled, single-factor laboratory settings.
Additionally, the complex multi-pathway regulatory nature of ERS,
coordinated by PERK, IRE1α and ATF6, combined with individual
heterogeneity among patients with DKD makes ‘precision targeting’ a
translational challenge. Laboratory studies often target single
pathways, whereas clinical ERS activation patterns vary notably
among patients with DKD: Some cases of DKD primarily involve
activation of the PERK/eIF2α pathway, accompanied by extensive
tubular epithelial apoptosis, while others predominantly involve
activation of the ATF6 pathway, accompanied by inflammatory
mediator release (for example, elevated IL-6 and TNF-α levels)
(71). Furthermore, ERS in DKD
involves glomerular mesangial cells, podocytes and tubular
epithelial cells; however, existing drugs exhibit systemic
distribution, complicating precise delivery to specific renal cell
subpopulations (18,19).
Addressing these bottlenecks requires further
research. Safety evaluations should incorporate multiple animal
models with renal insufficiency to more accurately replicate drug
metabolism characteristics observed in clinical populations. For
target optimization, kidney-specific drug formulations could be
developed to enhance renal tissue accumulation. Only through these
approaches can ERS inhibition strategies transition from being
mechanistically effective in laboratory settings to being safe and
beneficial in clinical practice.
The active constituents of TCM, such as AS and
Huangkui total flavonoids, exert multi-target modulatory effects on
ERS, including the downregulation of CHOP and inhibition of IRE1α
phosphorylation (47,166). These compounds also exert
antioxidant, anti-inflammatory and podocyte-protective effects,
supporting clinical evidence of reduced proteinuria and delayed
renal function decline in DKD. Such findings underscore the
potential of TCM-Western medicine integration as a promising
research avenue for DKD management. The development and translation
of ER-specific reagents targeting protein folding, UPR signaling
and ER calcium homeostasis hold promise for novel therapeutic
strategies (7).
In future research, it is important to investigate
ERS biomarkers for early DKD diagnosis by elucidating the
underlying ERS mechanisms. BiP/GRP78, as a sentinel protein for ERS
activation, exhibits increased expression levels that signal early
ERS and are directly associated with the severity of renal
pathological damage in DKD, thereby providing a foundational
reference for assessing disease progression (112). Concurrently, p-PERK, p-eIF2α and
ATF4 from the PERK pathway, p-IRE1α and XBP1s from the IRE1α
pathway and ATF6f (a type II transmembrane protein that under ER
stress is translocated to the Golgi apparatus where it is
proteolytically processed, releasing the cytoplasmic fragment of
ATF6) (77). from the ATF6 pathway
indicate the activation status of the three principal UPR branches,
accurately reflecting the ERS-mediated pathological transition from
adaptive protection to apoptosis initiation. The comprehensive
assessment of these markers not only clarifies the molecular
mechanisms of ERS in DKD but also provides molecular evidence for
staging disease progression (16).
These biomarkers thus hold potential for translation into early
diagnostic tools and therapeutic efficacy-monitoring indicators for
DKD, enabling precise clinical interventions. Simultaneously, the
development of inhibitors targeting specific pathways, such as
IRE1α-specific inhibitors, is important, offering novel therapeutic
strategies for DKD management. Given the growing potential of
ERS-targeted therapies, focused clinical studies are required to
deepen the current understanding of DKD pathogenesis and refine
targeted interventions. Collectively, these efforts will advance
DKD treatment and provide insights that are relevant to broader
ERS-associated disorders.
Not applicable.
The present study was supported by the Jilin Province Science
and Technology Development Program (grant no. 20210101201JC).
Not applicable.
PZ contributed to writing the manuscript and
prepared the figures. YZ made substantial contributions to the
conception and design of the study, conducting a comprehensive and
systematic literature review to identify key studies and ensuring
the research was grounded in relevant and current findings in the
field of DKD. YZ also played a crucial role in the analysis and
interpretation of data, particularly in understanding the
mechanisms of ERS in DKD. Additionally, YZ contributed to drafting
significant portions of the manuscript and critically revised it
for important intellectual content. YZ approved the final version
of the manuscript and takes full responsibility for the integrity
and accuracy of the work, ensuring all aspects of the research were
thoroughly addressed. CC, YC, FL, SZ and CL revised the manuscript.
All authors read and approved the final version of the manuscript.
Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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