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Current Protein & Peptide Science
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Current Protein and Peptide Science, 2023, 24, 2-6
PERSPECTIVE
A Perspective on the Impact of Advanced Glycation End Products in the
Progression of Diabetic Nephropathy
1875-5550/23 $65.00+.00 © 2023 Bentham Science Publishers
Afreen Khanam1, Saheem Ahmad2, and Arbab Husain1,*
1Department of Biotechnology & Life Science, Institute of Biomedical Education & Research, Mangalayatan University,
Aligarh, Uttar Pradesh, India; 2Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Uni-
versity of Hail, Hail-2440, Saudi Arabia
Abstract: In 2007, diabetes affected around 244 million people across the globe. The number of dia-
betics worldwide is projected to reach 370 million by 2030. With diabetes incidence reaching epidemic
proportions globally, diabetic nephropathy (DN) has emerged as one of the most difficult health condi-
tions. Although therapeutic approaches such as rigorous blood glucose and blood pressure management
are successful in preventing DN, they are far from ideal, and the number of diabetic patients with end-
stage renal disease continues to grow. As a result, a unique treatment approach for DN should be de-
vised. There is mounting evidence that advanced glycation end products (AGEs), senescent macro pro-
tein derivatives generated at an accelerated pace in DN, contribute to DN by generating oxidative
stress. The purpose of this article is to discuss the pathophysiological significance of AGEs and their
receptor in DN.
A R T I C L E H I S T O R Y
Received: June 09, 2022
Revised: August 26, 2022
Accepted: September 06, 2022
DOI:
10.2174/1389203724666221108120715
Keywords: Diabetes mellitus, diabetic nephropathy, glycation, AGEs, RAGE, renal disease.
1. INTRODUCTION
Diabetes nephropathy is the most common cause of end-
stage renal disease globally and may contribute to the disa-
bility and high death rate associated with diabetes. Accord-
ing to the World Health Organization, the worldwide diabe-
tes population will reach 370 million by 2030 [1]. Current
treatment alternatives, however, are far from adequate, and
the results of rigorous therapy on DN are inadequate. Indeed,
extensive management of blood glucose and/or blood pres-
sure is often difficult to maintain in diabetic patients and
may raise the risk of hypoglycemia and/or hypotension, and
the number of diabetic patients with end-stage renal failure
continues to rise in developed nations. As a result, the devel-
opment of innovative treatment techniques that are specifi-
cally targeted at DN is essential [2].
Throughout their lifespan, proteins and polypeptides are
frequently exposed to a variety of post-translational changes,
including phosphorylation, glycation, deamination, ubiquiti-
nation, and sumoylation [3]. These post-translational chang-
es may aid proteins in folding and sorting into diverse cellu-
lar compartments, trigger intracellular signaling, confer sta-
bility under stress circumstances, and regulate their intracel-
lular levels via degradation and control [4]. Proteins are also
subject to post-translational alterations that may affect their
*Address correspondence to this author at the Department of Biotechnology
& Life Sciences, Institute of Biomedical Education & Research, Man-
galayatan University, Aligarh, Uttar Pradesh, India;
E-mail: arbabhusain1@gmail.com
structure, function, and half-life due to natural aging and
pathological diseases such as diabetes. Glycation is one such
post-translational modification. Glycation of client proteins
results in crosslinking and aggregation, which may have a
detrimental effect on proteins' structural and functional char-
acteristics [5]. Along with altering the physicochemical
characteristics of the affected proteins, glycation causes ab-
normal cellular signaling, transcription factor activation, and
alterations in gene expression patterns. The end products
formed as a result of glycation are referred to as AGEs [6].
Even though glycation occurs at a slower rate throughout
life, it accelerates in clinical conditions such as diabetes and
is implicated in the pathophysiology of several diabetes
complications and other age-related disorders such as cata-
racts, nephropathy, cardiovascular complications, and Alz-
heimer's disease [7]. In individuals with T2DM, tissue AGEs
are highly correlated with early kidney, ocular, and nerve
damage [8].
2. AGEs AND DN
Both clinical and experimental evidence suggests that
AGEs are involved in the etiology of diabetic complications,
particularly DN, in type 1 and type 2 diabetes [9]. DN is the
most prevalent microvascular chronic complication, occur-
ring in 20%–40% of type 1 and type 2 diabetes mellitus
(T2DM) patients, respectively. Around one-third of all new
instances of end-stage renal disease (ESRD) are caused by
DN [10]. Affected glomerular capillaries result in a gradual
loss in glomerular filtration rate, which is followed by many
A Perspective on the Impact of Advanced Glycation End Products Current Protein and Peptide Science, 2023, Vol. 24, No. 1 3
stages of proteinuria, including microalbuminuria, macroal-
buminuria, and overt proteinuria, and ultimately resulting in
ESRD necessitating renal replacement. Hyperglycemia and
hypertension, which are also characteristics of T2DM, exac-
erbate the progression to ESRD [11]. Renal disease is char-
acterized by both hemodynamic (hyperfiltration) and struc-
tural abnormalities in diabetic patients. Significant glomeru-
lar alterations include basement membrane thickening,
mesangial enlargement and hypertrophy, and podocyte loss
[12]. The tubulointerstitial compartment undergoes signifi-
cant alterations throughout DN, including tubular basement
membrane thickening, tubular atrophy, interstitial fibrosis,
and arteriosclerosis [13]. The crucial involvement of AGEs
in the etiology of renal damage was shown in work in nondi-
abetic rats, where AGEs generated proteinuria and degenera-
tive alterations similar to those seen in DN. When type 1
diabetes patients progress from normal renal function to
ESRD, blood levels of fluorescent-CML AGEs rapidly rise.
In contrast, another research discovered a correlation be-
tween CML and the severity of nephropathy in type 1 diabe-
tes individuals. There is a considerable rise in CML and hy-
droimidazolone-AGEs in T2DM individuals. Serum CML-
human proteins were significantly higher in individuals with
proteinuria, and a rise in circulating AGEs peptides was as-
sociated with the degree of renal impairment [14]. The sever-
ity of DN is related to the number of AGEs formed and the
number of receptors for advanced glycation end products
(RAGE) expressed in the glomerular and tubulointerstitial
compartments. Accumulation of AGEs in the kidney may
contribute to the gradual change of renal architecture and
loss of renal function in humans and rodents through many
processes, such as the cross-linking of matrix proteins and
activation of downstream signaling. The development of
AGEs on extracellular matrix proteins modifies both matrix-
matrix and cell-matrix interactions and is implicated in dia-
betic glomerulosclerosis. AGEs promote apoptotic cell death
and VEGF expression in human mesangial cells cultivated in
vitro, much like in pericytes, the retinal analogue of mesan-
gial cells. As mesangial cells occupy a central anatomical
position in the glomerulus and play a crucial role in main-
taining the structure and function of glomerular capillary
tufts, the AGEs-induced apoptosis and dysfunction of
mesangial cells may contribute in part to glomerular hyper-
filtration, an early renal dysfunction in diabetes [15]. Addi-
tionally, the course of DN is marked by a reduction in the
glomerular filtration rate (GFR). AGEs increase the synthe-
sis of asymmetric dimethylarginine (ADMA), an endogenous
inhibitor of nitric oxide (NO) synthase. Plasma ADMA lev-
els are favorably connected with serum AGEs levels and
were adversely correlated with endothelial function evaluat-
ed by flow-mediated vasodilatation. In addition, AGEs low-
ered the messenger RNA (mRNA) level of dimethylarginine
dimethylaminohydrolase (DDAH)-II, an enzyme for ADMA
degradation, decreased its overall enzymatic activity, and
increased ADMA, all of which were prevented by the antiox-
idant N-acetylcysteine. This implies that the AGE-RAGE-
mediated ROS production might be implicated in endothelial
dysfunction in diabetic ESRD patients partially by boosting
the ADMA formation via reduction of DDAH activity in
ECs [16]. The inhibition of renal NO generation by AGEs is
thought to be a factor in the reduced GFR [17].
3. AGEs AFFECT ECM METABOLISM AND CAUSE
DN
DN is distinguished by the accumulation of ECM in the
mesangium, tubular interstitium, and glomerular basement
membrane (GBM) [18]. AGEs disrupt the equilibrium of
ECM component production and breakdown, notably colla-
gen. Collagen is one of the most thoroughly researched pro-
teins for glycation modification. AGEs development occurs
as a result of intra and intermolecular crosslinks in collagen,
resulting in major structural alterations such as changed
packing density and surface charge, all of which result in
lower solubility [19]. Glycated collagen impairs its ability to
self-assemble and interact with sub-ECM components. Re-
duced flexibility of arterial vessel walls and capillaries in the
glomeruli results from impaired intermolecular interactions
within collagen fibers and other components of basement
membranes [20]. Glycation of collagen has long been linked
to the progression of diabetes-related secondary complica-
tions. How precisely such random glycations arise in dam-
aged tissues is currently poorly understood. Because most
fibrillar collagens have a sluggish turnover rate, they are
more sensitive to accumulating time-dependent glycations
and advanced glycation end products. It is hypothesized that
the latter contain cross-links that stiffen host tissues. Howev-
er, diabetic animal models had weaker tendons with de-
creased rigidity. Using targeted mass spectrometry (MS),
researchers discovered higher partial fructosyl-hydroxylysine
glycations at each of the helical domain cross-linking sites of
type I collagen in tissues from a mouse model of diabetes.
None of the other collagen lysine residues were glycated. In
the tendons of mice, type I collagen is intermolecularly
cross-linked by acid-labile aldimine linkages generated by
the addition of telopeptide lysine aldehydes to hydroxylysine
residues at positions α1(I)Lys87, α1(I)Lys930, α2(I)Lys87,
and α2(I)Lys933 of the triple helix. These findings indicate
that site-specific glycation of these specific lysines may sig-
nificantly impair normal lysyl oxidase–controlled cross-
linking in diabetic tendons, suggesting that such N-linked
glycations may alter the content and/or placement of mature
cross-links thereby having the potential to modify tissue ma-
terial properties [21]. Aside from influencing collagen me-
tabolism, AGEs impact the interactions of ECM components.
Glycation may disturb intra-ECM and cell-matrix interac-
tions, leading to decreased cell proliferation, altered cellular
adhesion, and loss of the epithelial phenotype [5]. The modi-
fication of numerous ECM proteins with AGEs hinders their
breakdown by matrix metalloproteinases, which contributes
to basement membrane thickening and mesangial expansion
[22].
Due to charge-charge repulsion, the ECM of podocytes
and renal capillaries is negatively charged, preventing serum
albumin leakage into the glomerular filtrate. Glycation and
buildup of AGEs in the ECM components of renal capillar-
ies, on the other hand, modify the electrostatic interactions
that result in altered vascular permeability to albumin [23].
Accumulation of AGEs in ECM components may trap plas-
ma proteins, lipoproteins, and immunoglobulins, impairing
normal renal function balance and aggravating glomerulo-
sclerosis. Glycated collagen from the basement membrane
promotes platelet aggregation. The detrimental effects of
AGE buildup on ECM components have also been shown in
4 Current Protein and Peptide Science, 2023, Vol. 24, No. 1 Khanam et al.
investigations using AGE breakers. ALT-711 and N-
phenacylthiazolium bromide cleavage of AGE-induced
crosslinks increased collagen solubility and decreased matrix
formation in the kidney [24]. In podocytes, tubular cells, and
mesangial cells, AGEs promote the expression of transform-
ing growth factor-β (TGF-β ). TGF-β is a pro-fibrotic factor
that increases type IV collagen, laminin, and fibronectin syn-
thesis [25]. Additionally, AGEs stimulate the production of
platelet-derived growth factor, which is pro-fibrotic. Apart
from hyperglycemia, glycoxidation and lipoxidation prod-
ucts, such as CML, pentosidine, and malondialdehyde-
lysine, also contribute to the formation of AGEs [26]. Col-
lectively, AGEs change the metabolism and expression of
ECM components, resulting in an advanced nephropathy
phenotype.
4. ROLE OF RAGE AND OXIDATIVE STRESS IN DN
There is mounting evidence that the AGE-RAGE axis
plays a role in DN development. Among the different kinds
of AGEs receptors, RAGE is a signal-transducing receptor
for AGEs that may play a role in mediating the inflammatory
responses induced by AGEs [27]. In diabetic individuals
with nephropathy, RAGE expression is increased in podo-
cytes and mesangial cells. Numerous animal investigations
have also shown that RAGE plays a critical role in the estab-
lishment and progression of DN [28]. Indeed, diabetic mice
overexpressing RAGE exhibit increasing glomerulosclerosis
and renal failure compared to diabetic littermates without the
RAGE transgene. Additionally, it was reported that activat-
ing RAGE in podocytes might result in increased VEGF
expression and increased attraction/activation of inflammato-
ry cells in diabetic glomeruli, resulting in albuminuria and
glomerulosclerosis [29]. Furthermore, it has been reported
that diabetic mice induced with dB/dB or streptozotocin de-
velop renal changes similar to those seen in human DN, in-
cluding glomerular hypertrophy, glomerular basement mem-
brane thickening, mesangial matrix expansion, connective
tissue growth factor (CTGF) overexpression, and NFκ-B
activation, all of which are prevented by the administration
of a neutralizing antibody raised against RAGE. Further-
more, the AGE-RAGE interaction may result in chronic acti-
vation of NFκB due to higher amounts of de novo produced
NFκBp65 overcoming endogenous negative feedback sys-
tems, thereby contributing to the persistence of diabetic kid-
ney damage [15]. RAGE interaction with AGEs results in the
formation of oxidative stress, which contributes to DN. AG-
Es bind with their particular cell-surface receptor, RAGE,
initiating a signaling cascade that activates the transcription
factor nuclear factor-kappa B (NF-κB), resulting in an in-
crease in the production of inflammatory cytokines such as
TNF-α. The ensuing rise in inflammation leads to cellular
dysfunction and tissue destruction. Furthermore, AGEs in-
hibit intracellular detoxification mechanisms, which result in
increased oxidative stress. This AGE-RAGE axis, through
activating NADPH oxidases and/or by other similar mecha-
nisms, also stimulates the generation of reactive oxygen spe-
cies (ROS), which exacerbate oxidative damage to cells [30].
Indeed, ROS are cytotoxic to renal cells and promote in-
flammatory and fibrogenic responses in diabetic kidneys
[31]. The generation of ROS by AGE-RAGE induces the
synthesis of pro-sclerotic growth factors such as TGFβ and
CTGF in mesangial and renal tubulointerstitial cells through
the mitogen-activated protein kinase (MAPK), NFκ-B,
and/or PKC pathways.
Recent research has demonstrated the significance of Di-
aphanous1 in mouse diabetic kidney disease (DKD). Similar
to results involving RAGE expression in DKD, it was dis-
covered that Diaphanous1 was expressed in the tubulo inter-
stitium and podocytes of the human and mouse diabetic kid-
ney. Streptozotocin produced T1D-like symptoms in Diaph-
anous1 deficient and wild-type mice. After 6 months, diabet-
ic Diaphanous1 null mice exhibited considerably less
mesangial sclerosis, podocyte effacement, glomerular base-
ment thickening, and urinary albumin excretion than diabetic
wild-type control animals. Examining the renal cortex of
diabetic mice indicated that deletion of Diaphanous1 greatly
decreased the expression of genes associated with fibrosis
and inflammation [32]. Additionally, it was recently discov-
ered that inhibiting NADPH oxidase with apocynin protects
the kidneys against AGE-induced damage in experimental
DN through a PKC-dependent pathway. Thus, inhibiting
NADPH oxidase-derived reactive oxygen species (ROS)
production provoked by the AGE-RAGE system may be a
potential therapeutic target for diabetic patients with
nephropathy [33, 34].
CONCLUSION
With the enormity of diabetes incidence, the impact of
diabetes on human health, and the relevance of renal func-
tion, it is critical to have effective diabetes prevention strate-
gies. The scarcity of inexpensive and effective renal treat-
ment for those with chronic kidney disease adds to the global
healthcare burden. The body of data suggests that AGEs play
a crucial role in the pathogenesis of DN. As a consequence,
evaluating the effectiveness and safety of anti-AGE drugs
such as AGE blockers/crosslink breakers, ACE inhibitors,
and sRAGE inhibitors is the preferred preventative medica-
tion for DN.
LIST OF ABBREVIATIONS
AGEs = Advanced Glycation End Products
DN = Diabetic Nephropathy
T2DM = Type 2 Diabetes Mellitus
RAGE = Receptor for Advanced Glycation End Products
ESRD = End Stage Renal Disease
CML = Carboxy Methyl Lysine
GBM = Glomerular Basement Membrane
ECM = Extra Cellular Matrix
ADMA = Asymmetric Dimethylarginine
DDAH = Dimethylarginine Dimethylaminohydrolase
TGF-β = Transforming Growth Factor-β
CTGF = Connective Tissue Growth Factor
MAPK = Mitogen-Activated Protein Kinase
A Perspective on the Impact of Advanced Glycation End Products Current Protein and Peptide Science, 2023, Vol. 24, No. 1 5
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
The author would like to acknowledge Mangalayatan
University, Aligarh, and the University of Hail, Hail, Saudi
Arabia.
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