Advances in Targeting the AGEs-RAGE Pathway for the Treatment of Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) represents the most severe microvascular complication of diabetes and is the leading cause of end-stage renal disease globally. Its pathogenesis is complex, and current treatments have limitations. Advanced glycation end products (AGEs) and AGEs receptor (RAGE), constitute a core mechanism driving DKD progression. AGEs accumulate abnormally in high-glucose environments. Upon activation, RAGE mediates oxidative stress, chronic inflammation, renal fibrosis, dysregulation of autophagy, and apoptosis through multiple signaling pathways, ultimately leading to damage to the glomerular filtration barrier and exacerbating renal injury from multiple dimensions. This paper aims to elucidate the role of the AGEs-RAGE pathway in DKD and systematically review therapeutic strategies targeting this pathway. These include AGEs antagonists, AGEs-RAGE axis modulators, RAGE ligand binding inhibitors, antibody-based therapeutics, and traditional Chinese medicine. Additionally, clinical studies of AGEs-RAGE axis-targeted drug therapies for DKD are analyzed. This paper provides theoretical foundations for developing novel therapeutic drugs in DKD.

Introduction

Diabetic kidney disease (DKD) is one of the most severe microvascular complications of diabetes mellitus (DM) and has become the leading cause of end-stage renal disease worldwide.1 With the continuous rise in diabetes prevalence, the incidence of DKD has also shown a significant upward trend, imposing a heavy burden on global public health systems. According to the diabetes global report, approximately 589 million adults aged 20–79 worldwide have diabetes.2 In 2024, approximately 3.4 million people worldwide died from diabetes or its complications, accounting for 9.3% of all-cause deaths among adults aged 20–79.2 In 2021, the age-standardized case-fatality rate for type 2 DKD globally was 5.72 per 100,000.3 DKD is characterized by kidney damage and persistent albuminuria/proteinuria, often accompanied by a decline in glomerular filtration rate (GFR) and hypertension in later stages.4 The pathogenesis of DKD is complex and multifaceted, involving high glucose, hyperlipidemic, advanced glycation end products (AGEs), hemodynamic abnormalities, inflammation, oxidative stress, and genetic factors.1,5,6 Besides, gut microbiota dysbiosis is considered a key factor in the onset and progression of DKD.7

In the context of clinical treatment, existing therapeutic strategies for DKD still have obvious limitations, such as difficulty in completely reversing renal function decline or preventing disease progression in advanced stages. Thus, recent research has made breakthroughs in developing novel targeted therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been shown in multiple clinical trials to reduce proteinuria and slow the progression of kidney disease.8,9 Besides, traditional Chinese medicine has also emerged as a promising direction in DKD management—current studies are focusing on its active components and formulae, exploring their potential mechanisms in regulating renal inflammatory responses, improving renal microcirculation, and further reducing proteinuria while protecting residual renal function.10

The AGEs and AGEs receptor (RAGE) are considered one of the core mechanisms in the development of chronic diabetic complications.11,12 The AGEs-RAGE axis not only accumulates extensively under hyperglycemic conditions,13 but also activates multiple inflammatory and oxidative stress pathways, such as nuclear factor kappa-B (NF-κB)14 and mitogen-activated protein kinase (MAPK), leading to pathological changes including tubulointerstitial fibrosis, and thickening of the glomerular basement membrane.12 Consequently, increasing research focuses on pharmacologically intervening the AGEs-RAGE pathway to delay or reverse DKD progression.15,16 Traditional Chinese medicine components, owing to their multi-targeted effects and minimal side effects, are emerging as new therapeutic drugs targeting the AGEs-RAGE pathway.14,17 Numerous phytochemicals have demonstrated inhibitory effects on AGEs formation or RAGE signaling in preclinical models.18,19 This review aims to summarize the mechanisms of the AGEs-RAGE pathway in DKD and explore intervention strategies and research progress related to these compounds, providing a theoretical basis for the development of novel therapeutic drugs.

AGEs-RAGE Pathway

Formation and Types of Advanced Glycation End Products

AGEs are heterogeneous molecular complexes formed through non-enzymatic reactions between reducing sugars and amino acids in proteins, lipids, and nucleic acids. This formation process is termed the Maillard reaction.11 The formation of AGEs is a complex multistep process that can be broadly divided into four steps. The reaction initiates with the non-enzymatic glycation of reducing sugars with protein amino groups.12,20 Initially, reducing sugars undergo a reversible Schiff base reaction with protein amino groups. Subsequently, the Schiff base undergoes rearrangement to form a more stable Amadori product. The Amadori product undergoes a series of complex reactions including oxidation, dehydration, cleavage, and cyclization, ultimately yielding irreversible AGEs. Under hyperglycemic conditions, this reaction accelerates, leading to abnormal accumulation of AGEs in the body.21,22

Based on their origin, AGEs can be categorized into two types: compounds ingested from food (exogenous AGEs, also known as dietary AGEs) and compounds generated within the body. The latter are referred to as endogenous AGEs. Based on precursor substances, endogenous AGEs can be further subdivided into: Glyoxal -derived AGEs; Methylglyoxal (MGO)-derived AGEs; and 3-Deoxyglucosone-derived AGEs.13

Among numerous AGEs, Nε-carboxymethyl lysine (CML) and Nε-carboxyethyl lysine (CEL) are the most prevalent non-crosslinked AGEs.20,23 CML, a classic representative of AGEs and a key component of diabetes-related metabolic toxicity products, was first identified in 1985 as characterized glycoxidation products.24,25 Additionally, 3-hydroxypyridinium and its cross-linked structure, pyridinoline, are also common AGEs structures in collagen.26

AGEs not only alter the physical properties of tissue proteins through their cross-linking structures but also bind to specific receptors, activating downstream signaling pathways to induce oxidative stress and inflammatory responses.27 Among these, the AGE epitope AGE10 is significantly elevated in patients with diabetic microvascular complications, potentially exacerbating vascular and renal damage by promoting glycation reactions.28

Structure and Function of RAGE

RAGE belongs to the immunoglobulin superfamily and is a multi-ligand-recognizing transmembrane receptor primarily localized on the cell surface, participating in various pathophysiological processes.29

Localization and Expression

Although RAGE was initially defined as a membrane-bound receptor, recent studies indicate that in normal rat central nervous systems confirmed that RAGE is not only localized to the cell membrane but also widely distributed in the nucleus and cytoplasm.30 This suggests it may participate in atypical functions such as intracellular signal regulation or gene expression modulation. RAGE is encoded by the AGER gene located within the major histocompatibility complex class III (MHCIII) region on chromosome 6.31 Its precise localization is within the 6p21 region of human chromosome 6.32 RAGE is widely expressed across diverse cell types, including endothelial cells, cardiomyocytes, renal tubular epithelial cells (RTECs), glomerular mesangial cells (GMCs), podocytes, and pancreatic islet endocrine cells.11,15,33–35 RAGE is also expressed in diverse immune cells, including macrophages, T cells, and antigen-presenting cells.33 Several studies indicate its abnormally high expression in various tumor cells, suggesting a potential role in the tumor microenvironment.29

Molecular Structure and Genetic Characteristics

The structure of RAGE primarily comprises three extracellular domains, one transmembrane region, and one intracellular domain.36 Its extracellular region comprises one V-type immunoglobulin domain (Vdomain) and two C-type immunoglobulin domains (C1 and C2). The Vdomain serves as the core ligand-binding region, featuring a positively charged, flexible structure that facilitates binding to negatively charged ligands. The C1 and C2 domains contribute to structural stability and assist in ligand recognition.31 These domains mediate ligand binding. The intracellular domain transmits ligand-binding signals into the cell, initiating downstream signaling pathways.37

Study has demonstrated significant associations between single nucleotide polymorphisms (SNPs) in the AGER gene and type 2 DM (T2DM) risk.38 A study utilizing nanopore sequencing and PCR-RFLP validation identified rs1800625 (located in the promoter region) as significantly associated with increased T2DM susceptibility (OR=2.104, p=0.041). This SNP may enhance AGEs-RAGE axis activation by increasing AGER gene transcriptional activity and upregulating RAGE protein expression. Additionally, rs2070600 (G82S), an exon SNP causing substitution of glycine at position 82 in the extracellular domain of RAGE with serine, may influence its binding affinity to AGEs, thereby regulating downstream signaling intensity.38

Isomeric Forms

RAGE exists in multiple isomeric forms (as shown in Figure 1). Full-length RAGE (FL-RAGE) is the transmembrane form that mediates signal transduction.36 Soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are the two primary soluble forms of RAGE, generated mainly through two mechanisms: proteolytic cleavage of membrane-bound RAGE or alternative splicing.39,40 They lack transmembrane and intracellular domains. These soluble forms can act as decoy receptors, binding to RAGE ligands and preventing their interaction with full-length RAGE on the cell surface, thereby inhibiting RAGE-mediated signaling pathways.41 Cleaved RAGE (cRAGE) is a soluble isoform generated by proteolytic cleavage of the membrane-bound FL-RAGE by proteases such as ADAM10. Together, cRAGE and esRAGE constitute total soluble RAGE (sRAGE).40 N-truncated RAGE (Nt-RAGE) is a membrane-bound isoform with its N-terminus truncated.42 Its function may differ from that of full-length RAGE, but the specific mechanism requires further investigation.

Figure 1.

Structural diagrams of RAGE and its various isoforms.

Abbreviations: FI-RAGE, Full-length RAGE; Nt-RAGE, N-truncated RAGE; S-RAGE, soluble RAGE.

Ligand-Mediated Activation of Signaling Pathways

Beyond AGEs, RAGE recognizes multiple endogenous ligands including S100/calgranulin family proteins, high-mobility group box protein 1 (HMGB1), β-amyloid, phosphatidylserine, and complement C1q.29,31,33,43 These ligands are typically released or upregulated during cellular stress, inflammation, and tissue injury.33,36,43,44 Within its intracellular domain, ligand-activated RAGE interacts with intracellular effector molecules such as diaphin-1 (DIAPH1) from the formin family, MAPKs, extracellular signal-regulated kinase 1/2 (ERK-1/2), and docking protein.31 These effector molecules further activate signaling pathways including MAPK, PI3K/Akt, JAK/STAT, and GSK3β, ultimately regulating the expression of multiple inflammation-, oxidative stress-, and fibrosis-related genes by activating transcription factors NF-κB and Sp1.45 Among these, the NF-κB pathway represents one of the most critical inflammatory signaling pathways following RAGE activation. Upon binding to ligands such as AGEs, HMGB1, RAGE induces reactive oxygen species (ROS) production and activates NF-κB, promoting the release of proinflammatory factors like TNF-α, IL-6, and IL-1β, thereby exacerbating chronic inflammatory responses and tissue damage.46

Mechanism of the AGEs-RAGE Pathway in DKD

The progression of DKD involves AGEs-RAGE pathway, MAPK and NF-κB synergistic regulation. The AGEs-RAGE pathway represents one of the core molecular mechanisms driving the onset and progression of DKD.11,12 Clinical studies confirm that compared to healthy individuals and patients with T2DM alone, those with T2DM complicated by DKD exhibit significantly elevated plasma levels of AGEs-related glycation products (such as fructosamine, protein carbonyls, and CML), with increased expression of membrane-bound RAGE (mRAGE) and sRAGE, while expression of the antagonistic esRAGE is reduced. Furthermore, the degree of AGEs-RAGE pathway activation positively correlates with the severity of renal damage in DKD.47 The following systematically elucidates the mechanisms of the AGEs-RAGE pathway in DKD across four dimensions: oxidative stress activation, enhanced inflammatory response, imbalance of apoptosis and autophagy, and direct injury effects.

Activation of Oxidative Stress

Oxidative stress can cause cell and tissue damage and plays a key role in the occurrence and progression of diabetes and its complications. AGEs are important inducers of oxidative stress. After AGEs specifically bind to mRAGE on the surface of renal tissue cells including GMCs and proximal tubular epithelial cells. They can activate intracellular signal cascades through conformational changes, disrupting the balance of the renal oxidative-antioxidant system and ultimately inducing renal cell damage and tissue remodeling.43

The AGEs-RAGE axis mainly regulates oxidative stress by activating NADPH oxidase to promote de novo synthesis of ROS.26 In addition, it inhibits the expression and activity of antioxidant enzymes, thereby reducing the clearance capacity of ROS in the kidney. In addition, in streptozotocin (STZ)-induced DKD model, the activation of the AGEs-RAGE axis has been proved to be a key pathway of renal injury. A high-glucose environment promotes the abnormal accumulation of AGEs in renal tissue. AGEs bind to RAGE and activate downstream signaling pathways. On the one hand, the AGEs-RAGE axis induces the production of ROS, disrupting the antioxidant defense system of renal tissue including decreased activity of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and increased level of malondialdehyde (MDA). On the other hand, this axis exacerbates the disorder of glucose and lipid metabolism, and finally manifests as renal dysfunction, and glomerular structural damage. This suggests AGEs-RAGE axis plays an important role in the progression of DKD.48

In a mouse GMCs (SV40-MES-13) model, a high-glucose environment induces the accumulation of AGEs and activates PKCβ signaling through RAGE (as shown in Figure 2). Activated PKCβ further induces the expression of renal-specific oxidase NOX4, leading to excessive production of ROS and imbalance of oxidative stress, and finally causes mesangial cell dysfunction and early glomerular pathological changes.18 In addition, AGEs can up-regulate the expression of ATP synthase β subunit (ATP5b) in renal tubular epithelial cells through RAGE, which may be a compensatory antioxidant mechanism. Studies have shown that ATP5b significantly reduces the expression of fibrotic factors induced by AGEs by maintaining mitochondrial function, promoting ATP synthesis, and inhibiting oxidative stress. On the contrary, knockdown of ATP5b significantly increases the expression of these factors and the activity of CTGF promoter, leading to aggravated renal fibrosis and impaired renal function.49

Figure 2.

Mechanistic diagram of the AGEs-RAGE pathway in DKD via oxidative stress.

Abbreviations: AGEs, Advanced Glycation End products; CAT, catalase; GMC, Glomerular Mesangial Cells; GSH, glutathione; MDA, Malondialdehyde; NADPH, Nicotinamide Adenine Dinucleotide Phosphate; NOX4, NADPH Oxidase 4; PKCβ, Protein Kinase C β; RAGE, Receptor for Advanced Glycation End products; ROS, Reactive Oxygen Species; RTEC, Renal Tubular Epithelial Cells; SOD, superoxide dismutase.

Although a large number of basic studies have clarified the molecular mechanism of the AGEs-RAGE axis regulating oxidative stress,18,49 the specific molecular pathway still needs further clarification. In addition, most animal models are based on T1DM, lack verification using human DKD tissue/blood samples to establish a connection with clinical outcomes, and fail to quantify the pathogenic weight of exogenous AGEs or the dynamic changes of this axis in different DKD stages. Future research should focus on these aspects to promote the transformation of basic mechanisms into clinical applications.

Enhanced Inflammatory Response

Chronic inflammation, causing extensive pathological effects on the body and being closely related to the occurrence and progression of various diseases.50 The AGEs-RAGE pathway is a key molecular switch regulating renal inflammatory response. After AGEs bind to mRAGE, they activate signaling pathways such as NF-κB and MAPK, inducing abnormal expression of pro-inflammatory factors and adhesion molecules, recruiting inflammatory cell infiltration, and promoting the development of DKD from early inflammation to advanced fibrosis11,43 (as shown in Figure 3).

Figure 3.

Mechanistic diagram of the AGEs-RAGE pathway in DKD via inflammatory response.

Abbreviations: AGEs, Advanced Glycation End products; ASC, Apoptosis-associated speck-like protein containing a CARD; GMC, Glomerular Mesangial Cells; IL-1β, Interleukin-1 β; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-18, Interleukin-18; MAPK, Mitogen-Activated Protein Kinase; MCP-1, Monocyte Chemoattractant Protein-1; MR, Mineralocorticoid Receptor; NF-κB, Nuclear Factor Kappa B; NLRP3, NOD-like receptor family, pyrin domain containing 3; RAGE, Receptor for Advanced Glycation End products; RTEC, Renal Tubular Epithelial Cells; TNF-α, Tumor Necrosis Factor alpha.

Clinical and animal studies have further verified this mechanism: in a high-fat and high-fructose diet -induced DKD model, the accumulation of AGEs (CML, Nε-carboxyethyllysine, CEL) in renal tissue and the up-regulation of RAGE expression activate the NF-κB pathway, inducing renal inflammation and renal interstitial collagen deposition.51 In the apoE⁻/⁻ mouse model, the AGEs-RAGE axis has been proved to be a key initiating mechanism of renal injury.52 A high-glucose and high-fat environment promotes the accumulation of AGEs in renal tissue.52 AGEs activate NF-κB signaling through RAGE, further inducing the assembly of NLRP3 inflammasome. This promotes its binding to ASC and caspase-1, leading to the activation of caspase-1 and the maturation and release of pro-inflammatory factors IL-1β and IL-18, ultimately triggering glomerular inflammatory damage and mesangial expansion, accompanied by increased blood glucose, cholesterol, and renal function markers.52 At the cellular level, methylglyoxal, a major precursor of AGEs, activates downstream signaling pathways by binding to RAGE in GMCs and RTECs.53 Research indicates that the AGEs-RAGE axis significantly upregulates pro-inflammatory factors (eg, IL-6, TNF-α, MCP-1) and pro-fibrotic factors (eg, TGF-β1, CTGF), activates the p38 MAPK pathway, downregulates epithelial markers like E-cadherin, and upregulates mesenchymal markers such as α-SMA, fibronectin, and vimentin, ultimately inducing epithelial-mesenchymal transition (EMT). This process simulates the pathological transformation of RTECs into mesenchymal cells observed in DKD.53

At the molecular mechanism level, AGEs can also upregulate GAS2L1a (Growth Arrest-Specific 2-Like 1a) expression in podocytes via RAGE, suggesting that GAS2 family proteins may participate in AGEs-induced mesangial cell inflammatory responses, further driving the progression of DKD.54 In general, it is still unclear whether the increase of AGEs precedes renal fibrosis, and longitudinal clinical studies are needed to verify the causal relationship between AGEs and renal fibrosis.

In the AGEs-induced renal injury model, the AGEs-RAGE axis has been confirmed to be the core initiating mechanism of renal fibrosis. After AGEs bind to RAGE, they induce the nuclear translocation of high mobility group box 1 (HMGB1), form a complex with RAGE, and further activate the NF-κB pathway.55 This up-regulates the expression of TGF-β1 and enhances the deposition of extracellular matrix (ECM) through the phosphorylation of Smad2/3, thereby inducing renal fibrosis. At the same time, this axis down-regulates antioxidant pathways involving Sirt-1, GLP-1R, and Nrf2/HO-1, thereby exacerbating oxidative stress and inflammatory responses.55 In HEK 293 cells, treatment with AGE-BSA for 12 hours significantly up-regulated the expression of IL-6, and further induced an increase in IL-8 level after 24 hours. At the same time, the expression of NF-κB p65, RAGE, and HSP70 increased, accompanied by glutathione depletion, MDA increase, and enhanced antioxidant enzyme activity, suggesting that AGEs significantly induce oxidative stress and inflammatory responses.56

Furthermore, AGEs can trigger the release of inflammatory mediators such as TNF-α, IL-6, and MCP-1, recruiting monocyte/macrophage infiltration to form a chronic inflammatory microenvironment that exacerbates renal tissue damage.57 Notably, aldosterone promotes the formation of CML by enhancing the glycation modification of human serum albumin, which is confirmed by the increase of fructosamine, carbonyl content, and fluorescent AGEs. The AGEs-aldosterone complex also up-regulates the mRNA and protein expression of RAGE and mineralocorticoid receptor (MR), and enhances downstream signaling through the RAGE-MR pathway.58 Further studies have shown that activated RAGE and MR promote the expression of small G protein Rac-1, and then activate the NF-κB pathway to induce the release of pro-inflammatory factors and the production of ROS, forming a positively regulated signal network.58

As a representative AGE product, CML significantly activates the RAGE pathway. Clinical studies have shown that DKD patients and T2DM patients have high responsiveness to CML, manifested by significantly up-regulated CML-induced NF-κB gene expression, and significantly increased TNF secretion levels, while healthy controls have no significant changes.59 Such studies employ cross-sectional designs, demonstrating only the association between CML and inflammatory markers. However, establishing the causal sequence between elevated AGEs, inflammatory activation, and disease progression requires longitudinal clinical cohort studies.

D-ribose is a naturally occurring pentose monosaccharide. Compared with glucose, D-ribose is more likely to undergo glycosylation with proteins and rapidly form AGEs.60 The accumulation of AGEs activates RAGE, which in turn activates the NF-κB pathway, triggers an inflammatory response, leads to increased urinary nitrogen and creatinine levels in mice, and causes glomerular basement membrane thickening and mesangial matrix deposition.61 In addition, silencing RAGE in mesangial cells can block the phosphorylation of NF-κB.61 However, AGEs accumulation in human diabetes results from prolonged hyperglycemia and slow glycation, primarily involving glucose-derived glycation products. Furthermore, while pathological changes like glomerular basement membrane thickening occur within weeks in mice, human DKD progresses over years. Whether these findings can be extrapolated to humans requires further investigation.

In addition, the AGE derivative glyoxalate-derived pyridinium (GLAP) can also bind to RAGE, induce the production of ROS in proximal tubular epithelial cells, and up-regulate MCP-1 and pro-fibrotic factors PAI-1, ultimately leading to cell dysfunction.62 Future research should quantify the levels and pathogenic effects of different AGE derivatives in human diabetes, explore their pathogenic priority and specificity, and identify core intervention targets.

Imbalance Between Apoptosis and Autophagy

Apoptosis and autophagy are two types of programmed cell death or self-degradation processes, which play a crucial role in maintaining cell homeostasis, responding to environmental stress, and disease progression.63,64 In DKD, the AGEs-RAGE axis has been identified as a key mechanism inducing apoptosis and disrupting autophagy function (as shown in Figure 4). Renal homeostasis depends on the dynamic balance between apoptosis and autophagy. The AGEs-RAGE axis disrupts this balance by regulating apoptotic pathways and inhibiting autophagic clearance, thereby accelerating the progression of DKD.34,56

Figure 4.

Mechanistic diagram of the AGEs-RAGE pathway in DKD via apoptosis and autophagy.

Abbreviations: AGEs, Advanced Glycation End products; CHOP, C/EBP Homologous Protein; GRP78, Glucose-Regulated Protein 78; ER stress, Endoplasmic Reticulum stress; LC3-II, Microtubule-associated protein 3; p62/SQSTM1, Sequestosome-1; RAGE, Receptor for Advanced Glycation End products; ROS, Reactive Oxygen Species; RTEC, Renal Tubular Epithelial Cells; ΔΨm, Mitochondrial Membrane Potential.

The AGEs-RAGE axis induces renal cell apoptosis through multiple pathways: On one hand, the excessive ROS generated by this pathway activates mitochondrial membrane potential damage, releases cytochrome C, activates members of the caspase family (such as caspase-3 and caspase-9), and initiates the intrinsic apoptosis pathway; On the other hand, it activates the MAPK/ERK and JNK pathways, upregulating pro-apoptotic proteins Bax and downregulating anti-apoptotic proteins Bcl-2, thereby further promoting renal cell apoptosis.65,66 Experiments in NRK52E cells demonstrated that AGE-4 significantly induces apoptosis via the AGEs-RAGE axis, while siRAGE or ERK/JNK inhibitors effectively reverse this effect, confirming that AGEs-RAGE-mediated apoptosis depends on MAPK pathway activation.65 In human proximal tubular epithelial cells (HK-2), AGEs activate the endoplasmic reticulum stress (ERs) pathway by binding to RAGE, inducing the activation of the PERK-eIF2α-CHOP and IRE1 pathways, up-regulating ERs markers CHOP and GRP78, and enhancing the phosphorylation of NF-κB p65. This promotes the release of inflammatory cytokines and apoptosis, exacerbating tubular injury.66 Further studies have shown that in rat GMCs, the binding of AGEs to RAGE not only induces the production of ROS and the imbalance of the antioxidant system (decreased SOD activity, increased MDA) but also disrupts mitochondrial function, manifested as decreased mitochondrial membrane potential (Δψm), increased membrane permeability, and release of cytochrome C, ultimately activating the imbalance of Bax/Bcl-xL and the caspase-9/3 and PARP pathways to initiate apoptosis. In addition, the AGEs-RAGE axis up-regulates the expression of TGF-β1, promoting the deposition of type IV collagen and simulating glomerulosclerosis.19

The AGEs-RAGE axis primarily causes autophagy dysfunction by inhibiting autophagy flux. Autophagy serves as a critical pathway for cellular clearance of damaged organelles and toxic proteins.53 In age-related kidney injury models, AGEs accumulation downregulates AGER1 expression in GMCs. This simultaneously weakens AGEs clearance capacity and inhibits autophagy-mediated degradation of AGEs-modified proteins, leading to accumulation of injury byproducts and exacerbating renal cell damage and glomerulosclerosis.67 This dual effect of increased apoptosis, inhibited autophagy positions the AGEs-RAGE axis as a key mechanism disrupting renal cell homeostasis. Furthermore, AGEs activate ROS production via RAGE, induce elevated lysosomal membrane permeability, promote the release of cathepsins into the cytoplasm, reduce lysosomal acidification capacity, inhibit autophagic flux, and cause accumulation of LC3-II and ubiquitinated proteins, thereby further exacerbating tubular injury.68

In summary, AGEs disrupt the autophagy-lysosomal system through multiple RAGE-mediated signaling pathways, inducing apoptosis and functional impairment, thereby significantly accelerating the disease progression of DKD. However, most of the above studies focus on basic research. Future work should incorporate detection of autophagy-apoptosis markers in human DKD tissues to further explore clinical interventions based on this mechanism.

Direct Damage Mechanism

Studies have shown that after AGEs (such as AGE-BSA) bind to RAGE, they need the synergistic effect of αVβ3 integrin to effectively activate downstream signaling pathways. Specifically, after AGE-BSA binds to RAGE, it forms a complex with αVβ3 integrin, activates Src kinase, which in turn induces the activation of Rac1 and the production of ROS, and finally leads to podocyte damage.69 Mechanistic studies indicate a synergistic dependency between RAGE and αVβ3 integrin: in RAGE-deficient cells, soluble urokinase-type plasminogen activator receptor (suPAR) fails to effectively activate αVβ3 downstream signaling; while in αVβ3-deficient cells, AGE-BSA fails to activate the RAGE-mediated injury pathway. This indicates that the two form a “co-receptor complex”, serving as the key signaling platform for AGE-induced renal injury.69

Further studies have shown that the interaction between AGEs and RAGE activates the Notch1 signaling pathway. Specifically, activated RAGE mediates the release of the Notch1 intracellular domain (NICD1) through γ-secretase, inducing EMT in podocytes, which is manifested by down-regulated expression of E-cadherin and up-regulated expression of N-cadherin and vimentin.70 This process leads to thickening of the glomerular basement membrane, fusion of podocytes, and increased proteinuria. Notably, treatment with FPS-ZM1 (a RAGE inhibitor) or DAPT (a γ-secretase inhibitor) can effectively block this signaling pathway and significantly reduce the expression of renal fibrosis markers such as type IV collagen and α-SMA.70

In addition, CML can up-regulate the mRNA and protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), low-density lipoprotein receptor (LDLr), sterol regulatory element-binding protein-2 (SREBP-2), and its regulatory protein SCAP.71 The synergistic up-regulation of these molecules promotes cholesterol synthesis (mediated by HMG-CoAR) and uptake (mediated by LDLr), leading to abnormal lipid accumulation in the kidney and exacerbating renal injury.71

Further studies have shown that AGEs can also up-regulate the expression of GAS2L1a (Growth Arrest-Specific 2-Like 1a) in podocytes through RAGE, which may participate in podocyte cytoskeletal remodeling (eg, microfilament-microtubule cross-linking) and cell hypertrophy, thereby disrupting the structure and function of the glomerular filtration barrier.54 Urinary AGEs are significantly increased, which is strongly positively correlated with urinary sKlotho (r=0.81, p<0.05); the urinary albumin-to-creatinine ratio (UACR) is increased, indicating impaired integrity of the glomerular filtration barrier; serum sRAGE is decreased and urinary sRAGE is increased; the brush border of RTECs is damaged, impairing sKlotho transcytosis and increasing ADAM10-mediated cleavage, leading to increased urinary sKlotho and decreased serum sKlotho; RAGE protein expression in renal tissue is up-regulated, but Klotho expression remains unchanged; the Wnt pathway is in an inactive state, and no significant collagen deposition is observed, suggesting that this model represents the early stage of DKD.72

AGEs activate multiple pathogenic signaling pathways by binding to RAGE (as shown in Figure 5). For example, the fibrosis pathway is activated by up-regulating fibrosis markers such as CTGF, α-SMA, and fibronectin, accelerating the deposition of renal interstitial ECM. At the same time, the EMT pathway is also activated: by down-regulating E-cadherin, up-regulating vimentin, and increasing the transcription factor Snail, cellular phenotype transformation is induced.66 High-glucose also induces glycosylation modifications in transferrin at 17 sites, forming AGEs products such as CML and MG-H1. AGE-transferrin stimulation of HK-2 cells induces increased apoptosis, decreased total antioxidant capacity and GSH levels, and downregulates transferrin receptor expression, suggesting direct damage to RTECs.73 By binding to RAGE, AGEs induce collagen cross-linking, increased endothelial permeabilit, lipid metabolism disorders, and podocyte cytoskeletal remodeling, leading to impaired glomerular filtration function and renal injury. This makes AGEs one of the key drivers of DKD progression.

Figure 5.

Schematic diagram of the AGEs-RAGE pathway’s direct damaging mechanism in DKD.

Abbreviations: AGEs, Advanced Glycation End products; AGEs-Tf, Advanced Glycation End products-bound Transferrin; α-SMA, α-Smooth Muscle Actin; CTGF, Connective Tissue Growth Factor; ECM, Extracellular Matrix; EMT, Epithelial-Mesenchymal Transition; GAS2L1a, Growth Arrest-Specific 2 Like 1a; TGF-β, Transforming Growth Factor-β; Smad, Small Mothers Against Decapentaplegic; NF-κB, Nuclear Factor Kappa B; NICD, Notch Intracellular Domain; Notch1, Neurogenic locus notch homolog protein 1; RAGE, Receptor for Advanced Glycation End products; Tf, Transferrin.

Therapeutic Strategies Targeting the AGEs-RAGE Pathway

AGEs antagonists mainly intervene DKD progress by inhibiting AGEs synthesis, against MGO-induced glucotoxicity, or reducing ROS.74 Targeting the AGEs-RAGE pathway in DKD treatment involves multi-level interventions against its mediated cascade of oxidative stress, inflammation, and fibrosis, through midstream pathway blockade, precise receptor targeting, and natural multi-target regulation. These interventions form a complete chain, which can improve renal function by alleviating glomerular/tubular pathological damage, optimizing renal function indicators, and regulating plasma glucose and lipid to exert renal protective effects. Targeting the AGEs-RAGE pathway in recent years (Table 1).

Table 1.

Overview of Therapeutic Agents Targeting the AGEs-RAGE Pathway

Treatment Strategy	Specific Intervention Measures	Experimental Model	Effects	Primary Biological Effects/Renal Protective Effects	Ref
AGEs Antagonists	L-Cysteine	SV 40 MES13/MGO, HEK 293/MGO	MGO-AGEs formation↓ existing AGEs cross-links↓; MGO metabolism into D-lactic acid↑; Sirt1 ↑; Apoptosis↓, necrosis↓, and ROS↓,	Reduce MGO-induced renal cell apoptosis, necrosis and ROS production, and alleviate oxidative stress injury.	[74]
AGEs-RAGE Axis Modulators	Low-molecular-weight fucoidan (oligo-FO)	C57BL/6 mice/HF+STZ, NRK-52E/AGE	USP22 ↑, Sirt1↑, AMPK phosphorylation↑, HMGB1/HIF-1α nuclear translocation↓, RAGE↓; Nrf2 nuclear translocation↑, Keap1↓, and activates the Nrf2/HO-1↑; GLP-1R↑, TGF-β1/Smad2/3 pathway↓ Sirt1↑. fibrosis↓ and antioxidant effects↑.	Exert anti-renal fibrosis and antioxidant effects, blocking the formation of the “AGEs-HMGB1-RAGE” complex.	[55]
	Pyridoxamine (Pyr)	C57Bl/6J mice/fat and fructose	CML↓, CEL↓, RAGE↓; inflammatory↓, blood glucose↓, cholesterol↓;	Reduce renal inflammation and interstitial fibrosis, alleviate tubular injury, and lower serum creatinine (Scr) and urinary albumin levels.	[16,51]
	Pioglitazone (PIO)	Diabetic apoE (-/-)	AGEs↓ and RAGE↓; NF-κB↓, NLRP3 inflammasome↓, caspase-1↓, IL-1β↓, IL-18↓; blood glucose↓, cholesterol↓, BUN↓, and creatinine levels↓.	Reduce glomerular inflammation and mesangial expansion, lower blood glucose, cholesterol, BUN, and creatinine levels.	[52]
	Exenatide (GLP-1 analog)	PBMCs T2DM patients	Insulin secretion↑, lowers blood glucose↓, and AGEs substrates↓; serum AGEs levels↓, AGEs binding to RAGE↓, TGF-β/VEGF expression↓.	Inhibit AGEs-RAGE-mediated renal fibrosis and protect glomerular filtration function	[75]
	Empagliflozin (SGLT2 inhibitor)	db/db mice	AGEs↓, RAGE↓, NADPH↓, inflammatory↓, and fibrotic reactions↓.	Glomerular extracellular matrix accumulation↓, podocyte loss↓, proteinuria↓, and tubulointerstitial damage↓.	[76]
	Rosuvastatin	SD rats/STZ	Renal oxidative↓, inflammatory↓, and apoptotic statuses↓. HO-1↑	Succeeded in recovering kidney function and normal structure.	[77]
	Apasaban	Wistar rats/STZ	AGEs↓, RAGE↓, ROS production↓	Inhibit the cross-amplification effect of inflammation and fibrosis to mitigate renal injury.	[78]
	Flufenandrolone (AKF-PD)	db/db mice, HMCs/HG	AGEs↓, RAGE↓, fibronectin↓, PKCα/β↓, and NOX4 expression↓;	Reduce ROS production, protect mitochondrial function, and mitigate damage to GMCs.	[79]
	PPARδ agonist	RMCs/AGE-BSA	GLP-1R↑, RAGE↓, IL-6↓, TNF-α↓; AMPK/mTOR pathways↑, cellular hyperproliferation↓.	GLP-1R siRNA reverses its protective effect by mitigating AGEs-induced renal cell injury.	[80]
	Soluble RAGE (sRAGE)	C57bl/6 mice/STZ, AGE-BSA/PTCs	Phosphorylation of ERK1/2↑ and c-Jun↑	Suppress RAGE-mediated inflammation, oxidative stress, and activation of the fibrosis pathway at the source	[81]
RAGE Ligand Binding Inhibitor	Zafirlukast	Rat renal mesangial cells/AGE-BSA	The levels of inflammatory cytokines↓, markers of oxidative stress↓, and cell apoptosis↓	Inhibits NF-κB nuclear translocation and caspase cascade reactions, thereby mitigating AGEs-induced mesangial cell injury.	[82]
	RAGE Adaptor	Wistar rats/STZ Human renal mesangial cells, THP-1 cells/ AGE-BSA	NADPH oxidase activity↓, inflammation/fibrosis gene expression↓.	1. Improve STZ-induced diabetic kidney disease pathology in rats (reduce proteinuria, podocyte injury, and ECM accumulation); 2. Inhibit AGEs-induced oxidative stress in human mesangial cells.	[83]
Gene therapy for RAGE.	RAGE siRNA	HEK293cells/AGEs	IL-β↓, TNF-α↓	Phospho-ERK1/2↓, phospho-NF-kB p65↓,	[84]
	RAGE siRNA	HK-2 cells/fructose	Bax↓, IL-β↓, IL-6↓, caspase-3↓, caspase-9↓, Bcl-2↑	p-NF-κB↓,	[85]
	Single-component
Natural plant extracts and traditional Chinese medicine	Curcumin	Wistar rats /STZ	PON1↑, SOD↑, and CAT activity↑, TBARS↓ and PCO↓; AGE-R1↑ and GLO1↑ to promote AGEs↓; Improve glucose and lipid metabolism.	Decrease urinary protein and GSH expression	[17]
	Acteoside	SD rats/STZ MPC-5/AGEs	PPARγ↑; β-catenin pathway↓, Snail-1↓, α-SMA expression↓.	Dose-dependent reduction of AGEs-induced podocyte apoptosis, restoration of synaptopodin levels, and inhibition of podocyte EMT	[86]
	Calycosin	Male db/db mice mTEC/ AGEs	IκBα phosphorylation↓, and NF-κB p65 nuclear translocation↓, TNF-α↓ and IL-1β transcription↓.	Reduce AGEs-induced inflammation in RTECs and improve glomerular structural damage	[14]
	Chrysin	Male db/db mice HRMC/ High glucose	AGEs deposition↓ and RAGE expression↓; 2. the TGF-β1/Smad2/3 pathway↓, ECM deposition↓; MMP-2/9 expression↓.	Improve matrix degradation imbalance and alleviate renal fibrosis	[87]
	Cinnamaldehyde	Wistar rats/STZ	AGEs formation↓, RAGE↓, NF-κB↓, IL-1β↓, TGF-β expression↓.	Improve metabolic indicators, reduce kidney inflammation and fibrosis	[88]
	Dieckol (DK)	Mouse GMCs/MGO	AGE formation↓ and collagen↓; Competitively inhibits AGE-RAGE binding, the Nrf2/Glo-1/ARE pathway↑; MAPK phosphorylation↓.	Reduce ROS production and apoptosis, enhance antioxidant capacity	[35]
	Psoralea corylifolia L. seed (PCS)	SV40 MES 13/AGEs	AGEs-induced mesangial cell proliferation↓, cyclin A2/D1/E1↓; TGF-β1↓ and fibronectin expression↓, RAGE↓, NOX4↓, and NF-κB↓.	Reduce ROS production, alleviate mesangial cell hypertrophy and fibrosis in the glomerulus	[89]
	Esculetin	SD rats/STZ	TG↓, T-CHO↓, LDL↓; IL-1/6↓, ICAM-1↓, and NO↓; AGEs accumulation↓, AGEs-RAGE-mediated oxidative stress↓.	Reduce kidney inflammation and alleviate AGEs-related kidney damage	[90]
	Eucommia Extract	C57BL/6 mice/STZ NRK 52E/ AGEs	AGEs↓, MGO levels↓ Glo1 activity↑; Nrf2 pathway↑; TGF-β1↓, NF-κB↓, and p38MAPK pathway↓s.	Alleviate AGEs-RAGE-mediated oxidative stress and inflammation, and improve renal tissue apoptosis and structural damage.	[91,92]
	Cirsium japonicum Extract (CJ)	SD rats/STZ	CML↓ and CEL↓ in liver and kidney tissues; AGEs-RAGE binding↓; NOX4/p47phox ↓and MAPK↓.	Reduce ROS production to mitigate liver and kidney damage	[93]
	Quercetin	db/db mice	Bax↓, c-caspase3↓, Bcl-2↑, phosphorylation of EGFR↓ and ERK1/2↓		[67]
	Ishige okamurae Extract (IOE) and IPA	Mouse GMCs/MGO	AGEs↓, collagen cross-linking↓; Nrf2/ARE pathway↑, HO-1↑ and NQO1↑; Bcl-2/Bcl-xL↑, Bax/Caspase-3/7↓.	Reduce IL-6/TNF-α release and improve renal cell apoptosis	[94,95]
	Lagerstroemia speciosa extract (LSE)	SD rats/STZ and high-fat diet	AGEs↓, oxidative stress↓, GSH↑, decrease MDA/ROS↓; TNF-α/IL-6/IL-1β↓; Improve glucose and lipid metabolism.	Reduces Scr and BUN levels in STZ-induced rats, increases albumin levels, and alleviates the progression of DKD.	[96]
	Grape Seed Proanthocyanidin Extract (GSPE)	Wistar rats/STZ	Serum AGEs↓, renal cortical RAGE expression↓; Upregulates nephrin↑,	Improving glomerular basement membrane thickness and podocyte foot process structure. Inhibits mesangial matrix accumulation. Reduced 24-hour urinary albumin, and delayed glomerulosclerosis	[97]
	Dipsacus polysaccharide (DAP)	Wistar rats/STZ	FBG↓, HbA1c↓, AGEs production↓, RAGE↓ in renal tissue; 2. Regulates blood lipids TC↓, TG↓, LDL-C↓, HDL-C↑; SOD/CAT/GSH activity↑.	Dose-dependent improvement in renal hypertrophy and glomerular damage (300 mg/kg showed optimal efficacy), comparable to metformin.	[48]
	Kaempferol (KM)	GMCs/AGEs	RAGE↓, ROS↓; mitochondrial damage↓, Caspase-9/3/PARP↑; TGF-β1↓, Collagen IV↓.	Reverses the AGEs-induced decline in GMCs viability and reduces ECM accumulation.	[19]
	Swertiamarin (SM)	NRK-52E/MG	Nrf2/HO-1↑, ER stress↓	Blocking EMT in NRK-52E cells restores cellular vitality and morphology.	[53]
	Puerarin (Pu)	SV40-MES-13/ High glucose	AGEs↓, RAGE↓; PKCβ activation↓, NOX4 ↓.	Dose-dependent alleviation of oxidative stress	[18]
	Celastrol	NRK-52E/ High glucose	It blocks the AGEs-RAGE pathway; TNF-mediated inflammation↓, AKT1-mediated apoptosis↓, MAPK3-mediated fibrosis↓.	Improving high-glucose induced damage to RTECs.	[98]
	Compound Formulas and Drug Pairings
	Jiangtang decoction	KK-Ay mice, C57BL/6J mice	AGEs↓, RAGE↓; PI3K/AKT↑, insulin resistance↓; NF-κB↓, IL-6↓, TNF-α↓.	Multi-target approach delays DKD progression and improves renal function indicators	[99]
	Radix Rehmanniae and Corni Fructus	KK-Ay mice, C57BL/6J mice	ROS/NF-κB↓, RAGE↓, AGEs-RAGE-NF-κB-IL-17 pathway↑.	Reduce kidney inflammation and fibrosis, promote insulin secretion to decrease AGEs formation	[100]
	Nardostachyos Radix et Rhizoma-rhubarb drug pair	TCMK-1 cells (renal tubule epithelial cells)/ High-glucose	BCL2↑, Bax↓, Caspase9/3↓; CyclinD1/CDK4 ↓	Improving DKD damage to RTECs through inflammation, apoptosis, and cellular hypertrophy	[101]

Notes: ↓ indicates inhibition/reduction while ↑ indicates increase/promotion.

Abbreviations: AGEs, Advanced Glycation End products; AMPK, AMP-activated Protein Kinase; α-SMA, α-Smooth Muscle Actin; Bax, BCL2-Associated X Protein; Bcl-2/Bcl-xL, B-cell Lymphoma 2/B-cell Lymphoma-extra Large; BSA, Bovine Serum Albumin; BUN, Blood Urea Nitrogen; CAT, Catalase; CDK4, Cyclin-Dependent Kinase 4; CEL, Nε-carboxyethyl lysine; CML, Nε-carboxymethyl lysine; ECM, Extracellular Matrix; ERK1/2, Extracellular Signal-Regulated Kinases 1/2; FBG, Fasting Blood Glucose; GLP-1R, Glucagon-Like Peptide-1 Receptor; Glo-1, Glyoxalase 1; GSH, Glutathione; HbA1c, Glycated Hemoglobin A1c; HIF-1α, Hypoxia-Inducible Factor 1-α; HMGB1, High Mobility Group Box 1; HO-1, Heme Oxygenase-1; ICAM-1, Intercellular Adhesion Molecule 1; IkBα, Inhibitor of Kappa B α; IL-18, Interleukin-18; Keap1, Kelch-like ECH-associated Protein 1; L-LDL, Low-density Lipoprotein; MAPK, Mitogen-Activated Protein Kinase; MDA, Malondialdehyde; MGO, Methylglyoxal; MMP, Matrix Metalloproteinase; NADPH, Nicotinamide Adenine Dinucleotide Phosphate; NF-kB, Nuclear Factor Kappa B; NO, Nitric Oxide; NOX4, NADPH Oxidase 4; NQO1, NAD(P)H Quinone Dehydrogenase 1; Nrf2, Nuclear Factor Erythroid 2-Related Factor 2; PARP, Poly (ADP-ribose) Polymerase; PKCα/β, Protein Kinase C α/β; PON1, Paraoxonase 1; PPARγ, Peroxisome Proliferator-Activated Receptor γ; p47phox, Neutrophil Cytosolic Factor 1; PTCs, Proximal Tubular Cells; RAGE, Receptor for Advanced Glycation End products; ROS, Reactive Oxygen Species; RTECs, Renal Tubular Epithelial Cells; Sirt1, Sirtuin 1; Smad2/3, Mothers Against Decapentaplegic Homolog 2/3; Snail-1, Snail Family Transcriptional Repressor 1; STZ, Streptozotocin; T-CHO, Total Cholesterol; TG, Triglycerides; TGF-β, Transforming Growth Factor β; TGF-β1, Transforming Growth Factor β 1; TNF-α, Tumor Necrosis Factor α; VEGF, Vascular Endothelial Growth Factor.

However, there are still significant gaps in current research: only a few strategies have clinical data, while most are still in the cellular/animal experimental stage; in addition, the detailed mechanism of some natural components is still unclear, and there is a lack of research on dose individualization. While many herbal compounds show promise in vitro, their poor oral bioavailability and potential herb-drug interactions warrant caution in clinical application. Future efforts should focus on promoting the clinical transformation of this pathway-targeted therapy through large-scale Phase III clinical trials, exploring combined therapy strategies, and analyzing the mechanism of natural components.

Clinical Research Progress on Drugs Targeting the AGEs-RAGE Axis

Currently, multiple clinical studies have focused on the mechanism of AGEs and their receptor RAGE in DKD, exploring potential therapeutic strategies for intervening in this pathway. A search on ClinicalTrials.gov (National Institutes of Health) shows seven clinical studies on AGEs and DKD, and two studies on RAGE and DKD (Table 2).

Table 2.

Overview of Clinical Studies Targeting the AGEs-RAGE Pathway for DKD Treatment

NCT Number	Study Status	Conditions	Interventions	Mechanism	Phases	Enrollment	Start Date	Primary Completion Date
NCT04084886	Unknown	DKD	Not Applicable	Not Applicable	Not Applicable	100	2019/9	2020/9
NCT00967629	Completed	DKD	DRUG: Sevelamer Carbonate|DRUG: Calcium Carbonate	Reduce inflammation and oxidative stress.	PHASE1	20	2009/6	2010/2
NCT00320060	Completed	DKD	DRUG: Pyridorin (pyridoxamine dihydrochloride)	Not Applicable	PHASE2	128	2001/1	Not Applicable
NCT00320021	Completed	DKD	DRUG: Pyridorin (pyridoxamine dihydrochloride)	Not Applicable	PHASE2	80	2002/7	Not Applicable
NCT00320970	Completed	DKD|Hypertension	DRUG: Candesartan	TGF-β1	Not Applicable	36	2002/8	2004/09
NCT06376240	Recruiting	T2DM|Microvascular Function|Retinopathy, Diabetic|Nephropathy, Diabetic|Neuropathy, Diabetic	DIETARY_SUPPLEMENT: Pyridoxamine 300mg per day|OTHER: Placebo 300mg placebo per day	Not Applicable	Not Applicable	40	Not Applicable	Not Applicable
NCT03622762	Unknown	DKD	DRUG: green tea extract|DRUG: Placebo	Not Applicable	PHASE2	30	Not Applicable	Not Applicable
NCT01371955	Completed	T1DM |DKD	Not Applicable	Not Applicable	Not Applicable	162	2011/1	2013/3

Existing clinical studies cover multiple links of the AGEs-RAGE axis, including upstream AGEs production inhibition/clearance (eg, pyridoxamine, sitivastatin), midstream RAGE regulation (eg, green tea extract increasing sRAGE), and downstream genetic susceptibility exploration (eg, CF7L2, AGER gene polymorphisms), laying a foundation for pathway mechanism verification and therapeutic transformation. However, the reliability of evidence is still limited: most studies have small sample sizes (eg, only 39 cases in green tea extract research) and short follow-up periods, failing to verify long-term safety (eg, neurotoxicity risk of long-term use of pyridoxamine) or hard endpoint efficacy (eg, delaying the progression of ESRD), thus limiting the extrapolation of results. In addition, intervention timing only focuses on patients with established DKD, ignoring the potential of early prevention; the lack of strict control of concurrent medications (eg, SGLT2 inhibitors) makes it difficult to distinguish the independent therapeutic effect. Future research should carry out large-scale, long-term follow-up Phase 3 clinical trials with hard endpoints; standardize specific markers of the AGEs-RAGE axis and core renal function indicators; deepen mechanism research to establish causal relationships; and explore early intervention and combined therapy strategies to improve the strength of evidence and clinical transformation value.

Discussion and Outlook

The AGEs-RAGE signaling axis plays a central role in the occurrence and progression of DKD. In therapeutic exploration, small-molecule inhibitors, therapeutic antibodies and natural plant/traditional Chinese medicine components have shown potential for targeted regulation of the AGEs-RAGE pathway. Clinical studies of some drugs have confirmed that they can improve renal function markers in DKD patients, providing preliminary evidence for clinical transformation. However, current research still needs breakthroughs. First, the interaction between the AGEs-RAGE pathway and emerging mechanisms such as gut microbiota dysbiosis and epigenetic regulation is still unclear. Further clarification of the molecular network of multi-pathway synergistic regulation of DKD is needed. Second, studies lack systematic clinical data to support their in vivo pharmacokinetic characteristics, target specificity, and long-term safety.

The future research of the AGEs-RAGE axis has broad prospects. First, using technologies such as single-cell sequencing and proteomics, we can deeply explore new downstream effector molecules regulated by the AGEs-RAGE axis in DKD, providing more precise targets for drug development. Second, strengthen the structural modification and formulation optimization of natural bioactive compounds to improve their bioavailability and tissue targeting, and carry out multi-center randomized controlled trials to verify their clinical value. Third, explore the feasibility of AGEs-RAGE pathway-related molecules as biomarkers for early diagnosis and prognostic evaluation of DKD. Finally, we propose to develop strategies targeting the AGEs-RAGE pathway. These strategies, tailored to patients’ genetic background, DKD stage, and comorbidities, may provide new solutions for improving the long-term prognosis of DKD patients and reducing the global public health burden.

Funding Statement

This work was supported by the Science and Technology Program of the Joint Fund of Scientific Research for the Public Hospitals of Inner Mongolia Academy of Medical Sciences (grant number 2024GLLH1008); Natural Science Foundation of Chifeng (grant number SZR2025089); Innovative entrepreneurship program for college students at Chifeng University, (grant number S202510138019).

Disclosure

The authors report no conflicts of interest in this work.