Receptor for advanced glycation endproducts (RAGE) is a multiligand cell-surface receptor that belongs to the immunoglobulin superfamily, which is initially isolated from bovine lung as a binding protein of advanced glycation endproducts (AGEs) [1,2]. The extracellular domain of the receptor contains one V-type domain followed by two C-type immunoglobulin domains. Binding of AGEs to RAGE V-type and C1-type domains has been reported to stimulate the generation of reactive oxygen species (ROS) and subsequently enhance various intracellular pathways such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) via the activation of Diaphanous-1, Ras-related C3 botulinum toxin substrate-1 (Rac-1), and cell division cycle 42 (Cdc42), all of which are associated with the development and progression of diabetic nephropathy [3–5]. Furthermore, engagement of RAGE with other types of ligands also modulates various pathophysiological responses, including inflammatory and immune reactions, cell growth, migration, apoptosis, and regeneration [6,7▪]. Indeed, in addition to AGEs, the interaction of RAGE with high-mobility group box-1 (HMGB-1; a nuclear DNA-binding protein released from necrotic and inflammatory cells), S100/calgranulins (a family of nonubiquitous Ca2+-binding proteins), β-sheet amyloid fibril, and lipopolysaccharide (LPS) has been shown to exert deleterious effects on hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, renal amyloidosis, autosomal dominant polycystic kidney disease (ADPKD), and septic acute kidney injury (AKI) by inducing NADPH oxidase-mediated ROS generation and also NF-κB activation [8–15]. Therefore, the blockade of the ligands–RAGE interaction may be a novel therapeutic strategy for preventing numerous renal disorders. In this review, we discuss the pathophysiological role of RAGE in both diabetic and nondiabetic renal diseases, and its potential use for therapeutic interventions in these devastating disorders.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND DIABETIC NEPHROPATHY
There is accumulating evidence that AGEs and their receptor interactions play a role in diabetic nephropathy [12,16–19]. Among the various types of AGEs receptors, RAGE is one of the main cell-surface receptors for AGEs that can mediate the inflammatory and fibrotic reactions in several organs of the diabetic milieu. In humans, RAGE is expressed in the podocytes  and mesangial cells  in the kidneys of diabetic patients with nephropathy. Several animal studies have suggested that RAGE has a crucial role in the development and progression of diabetic nephropathy [14,15,18,19]. Diabetic RAGE transgenic mice exhibited accelerated glomerulosclerosis compared with their diabetic littermates . RAGE knockout mice failed to develop characteristic pathological changes in diabetic nephropathy such as increased matrix expansion in the mesangial areas and thickening of the glomerular basement membrane . Further, db/db or streptozotocin (STZ)-induced diabetic mice developed glomerular hypertrophy, thickening of the glomerular basement membrane, and mesangial matrix expansion in accordance with increased connective tissue growth factor (CTGF) expression and NF-κB activation, all of which are blocked by the administration of the neutralizing antibody raised against RAGE [21,22]. Recently, Tesch et al.[23▪▪] have reported that deletion of RAGE from bone-marrow-derived cells improves STZ-induced diabetic nephropathy by inhibiting macrophage infiltration and renal tubule interstitial damage. These findings suggest that RAGE might play a central role in the progression of diabetic glomerular and interstitial injury.
Oxidative stress evoked by the AGEs–RAGE axis acts as a second messenger in the renal cells including mesangial cells, podocytes, and tubulointerstitial cells [24,25], and elicits inflammatory and fibrotic reactions, thus causing participation in diabetic nephropathy [26,27]. Indeed, AGEs–RAGE-mediated ROS generation stimulates production of prosclerotic growth factors such as transforming growth factor-β (TGF-β) and CTGF via MAPK, NF-κB, and PKC pathways in both mesangial and renal tubulointerstitial cells [11,24,28,29]. Thallas-Bonke et al. have reported that the inhibition of NADPH oxidase by apocynin prevents AGEs-elicited renal damage in experimental diabetic nephropathy through a PKC-α-dependent pathway. Liebisch et al. have found that activation of RAGE by AGEs or other ligands suppresses the nuclear inhibitor of protein phosphatase-1 (NIPP1) expression and stimulates NF-κB activation in diabetic nephropathy, contributing to podocyte hypertrophy and glomerular infiltration. Further, Jha et al.[32▪▪] have recently shown that Nox4 is the main source of renal ROS production in STZ-induced apolipoprotein E (ApoE) knockout mice. Deletion of Nox4, but not Nox1, resulted in renal protection from glomerular injury, as evidenced by attenuated albuminuria, preserved renal structure, reduced glomerular accumulation of extracellular matrix proteins, inhibited glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in these mice, thus indicating that the RAGE–Nox4 axis may play a central role in the ROS-associated renal injury in diabetic patients [32▪▪].
Recently, we have found that administration of DNA-aptamer raised against AGEs (AGEs-aptamer) – a short, single-stranded DNA molecule that can bind with high affinity and specificity to AGEs-modified proteins – inhibits diabetes-induced ROS generation, AGEs accumulation, RAGE expression, and inflammatory changes in the kidney associated with the improvement of albuminuria and glomerulosclerosis in a type 2 diabetic animal . Furthermore, AGEs-aptamer inhibited the AGEs-caused oxidative, inflammatory, and fibrotic reactions in cultured mesangial cells by blocking the binding of AGEs to RAGE [33▪▪]. Moreover, AGEs-aptamer can improve glycaemic control and prevent adipocyte remodelling in fructose-fed rats, partly by suppressing the AGEs–RAGE-mediated oxidative stress generation . These findings suggest that the inhibition of the AGEs–RAGE axis by AGEs–DNA-aptamer may be a novel therapeutic strategy for preventing diabetic nephropathy.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND HYPERTENSIVE NEPHROPATHY
Hypertension-related nephropathy is one of the major causes of end-stage renal disease (ESRD), especially in elderly patients . Vascular hyalinization and medial wall thickening of renal arterioles and onion-skin lesions and fibrinoid necrosis in the glomeruli are the characteristic features of benign and malignant nephrosclerosis, respectively . Glomerular damages such as obstructive or collapse lesions and subsequent tubulointerstitial injury are the major pathological events leading to renal fibrosis and dysfunction . Abel et al. examined the expression of RAGE in the kidney biopsies of patients with hypertensive nephropathy. They showed that RAGE was more expressed in the glomeruli and tubulointerstitium of benign nephrosclerosis than diabetic nephropathy in the immunohistochemical analysis . Tanji et al. also reported that N-Carboxymethyllysine (CML), one of the well characterized nonfluorescent AGEs, accumulated in the kidneys of patients with hypertensive nephropathy.
The renin–angiotensin system (RAS) contributes to the endothelial dysfunction, an initial step in hypertensive nephropathy . We, along with others, have reported that there is cross-talk between the AGEs–RAGE system and RAS in the pathogenesis of both diabetic and nondiabetic renal and cardiovascular diseases [11,39▪,40]. Thomas et al. have demonstrated that the administration of angiotensin II (Ang II) significantly increases renal AGEs accumulation in rats, which was abolished by the administration of valsartan, an Ang II type 1 receptor blocker (ARB). Furthermore, Matsui et al. have shown that irbesartan, an another ARB, inhibits the AGEs-induced upregulation of vascular cell adhesion molecule-1 (VCAM-1) mRNA levels in the glomerular endothelial cells. Irbesartan also inhibits the AGEs-induced increase in the asymmetric dimethylarginine (ADMA) level in mesangial cells through its antioxidative properties . Therefore, hypertension might activate the pathological cross-talk between the AGEs–RAGE axis and RAS, thereby becoming involved in the progression of nephrosclerosis in hypertensive patients.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND OBESITY-RELATED GLOMERULOPATHY
Obesity is one of the strongest risk factors for chronic kidney disease (CKD) . Obesity-related glomerulopathy is characterized by glomerular hyperfiltration and hypertrophy, focal segmental glomerulosclerosis, and podocyte foot process effacement [44,45]. Clinical studies have demonstrated that obesity is associated with end-stage renal disease (ESRD) . Hall  reported that obesity increases renal sodium reabsorption and impairs pressure natriuresis by the activation of RAS. Further, insulin resistance in patients with obesity has been correlated with glomerular hyperfiltration . Although the mechanism for obesity-related glomerulopathy is not fully understood, the AGEs–RAGE axis might participate in the obesity-associated renal injury. Amin et al. examined serum CML levels in obese or nonobese patients with or without type 2 diabetes. They found that the serum levels of CML in the diabetic obese group were significantly higher than those in the diabetic nonobese group . A significant positive correlation was observed between CML and BMI and waist/hip ratio, thus suggesting that obesity per se can accelerate the CML accumulation independent of diabetic condition . Pioglitazone, one of the ligands of the nuclear transcription factor, peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to improve obesity-associated nephropathy in association with a decrease in oxidative stress generation, renal RAGE, and TGF-β mRNA expression in Zucker-fatty rats . Further, Harcourt et al. have demonstrated that obesity was correlated with an increase in urinary albumin excretion (UAE), hyperfiltration, enhanced CML accumulation, and mitochondrial and cytosolic superoxide generation in the kidneys, all of which were prevented in RAGE knockout obese mice. They also found that Alagebrium, a compound for AGEs cross-link breaker, suppressed the renal mitochondrial and cytosolic superoxide production, but not the increase in UAE, renal CML accumulation, or RAGE expression . The findings suggest that some other ligands than AGEs, such as S100/calgranulin and HMGB-1, might be involved in the pathogenesis of obesity-related renal disease . On the other hand, Hagiwara et al. reported that pyridoxamine (K-163), an AGEs inhibitor, improved glucose intolerance and insulin resistance by decreasing oxidative stress generation in high-fat diet C57BL/6j mice, thus suggesting that the AGEs–RAGE axis has a central role in insulin resistance in obesity.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND LUPUS NEPHRITIS
Systemic lupus erythematosus (SLE) is a severe, multisystem autoimmune disease characterized by the presence of several autoantibodies . Most patients with SLE have deposition of immunoglobulins and complements in the glomeruli of the mesangial area and basement membrane, which could stimulate mesangial and endothelial cell proliferation and extracellular matrix accumulation, and be involved in glomerular and tubulointerstitial damage [53▪▪,54]. RAGE may contribute to inflammatory reactions in autoimmune-associated renal diseases, including lupus nephritis [12,37]. In human samples of renal biopsy, RAGE and CML were overexpressed in the kidneys of patients with lupus nephritis [12,37]. HMGB-1 has been shown to be an essential component of DNA-containing immune complexes that could stimulate cytokine production through a Toll-like receptor (TLR)-9–myeloid differentiation primary response 88 (MyD88) pathway via the interaction with RAGE . In patients with SLE, HMGB-1–nucleic acids complexes are released from the necrotic cells, and immune complexes are deposited in the glomeruli, which is associated with enhanced inflammatory reactions in the kidney . Plasma levels of HMGB-1 and TNF-α in patients with lupus nephritis have been found to be higher than in healthy controls . Further, Abdulahad et al. have reported that urinary HMGB-1 produces disease activity in patients with lupus nephritis. Interestingly, Martens et al. have found that some RAGE polymorphism is linked to the susceptibility to SLE and lupus nephritis. These data support the concept that RAGE might play an important role in the pathogenesis of SLE and its related renal complications by mediating the inflammatory responses in the kidney via the interaction with HMGB-1.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND AMYLOID-RELATED KIDNEY DISEASE
Amyloids represent a family of proteins and about 20 different types of amyloid have been identified . Amyloids and their β-sheet fibrils have been reported to bind to RAGE as their ligand, whose interaction can participate in the neuronal cell death and microglial activation in a brain with Alzheimer's disease . β2-Microglobulin modified with AGEs is a major component of β2-microglobulin amyloidosis . Miyata et al. have demonstrated that the interaction of AGEs-modified β2-microglobulin with RAGE activates human mononuclear phagocytes via oxidant stress-sensitive pathways and is involved in dialysis-related amyloidosis. Serum levels of AGEs have been found to be increased in patients with chronic rheumatoid arthritis (RA) with amyloid A-type amyloidosis, compared with those with non-amyloid A-type amyloidosis . Further, AGEs accumulation and RAGE expression were enhanced in the amyloid deposits of the glomeruli in patients with amyloid A-type amyloidosis . In addition, serum levels of AGEs are increased in familial amyloidotic polyneuropathy (FAP) patients compared with age-matched healthy controls . Immunohistochemical analysis has revealed that AGEs deposition and RAGE expression were enhanced in the glomeruli and tubules of patients with FAP and Gelsolin amyloidosis, an autosomal dominant inherited systemic amyloidosis, which were co-localized with the extensive deposition of amyloid [10,65]. Therefore, RAGE activation might play a role in amyloid-related renal disease.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
ADPKD is one of the most highly prevalent inherited disorders, which is characterized by the development of numerous size-different fluid-filled cysts in the kidney . Increased cyclic adenosine monophosphate (cAMP) levels, activation of MAPK and Janus kinase (JAK)2–signal transducer and activator of transcription (STAT)1/3 signalling pathway, NF-κB activation, and vascular endothelial growth factor (VEGF) production have been supposed to play a role in the cystogenesis in ADPKD [67,68]. Recently, Park et al. showed that renal RAGE, S100 calcium-binding protein A8 (S100A8), and S100A9 gene expression are elevated in polycystic kidney 2 (PKD2) transgenic mice. Moreover, the administration of adenovirus containing anti-RAGE small hairpin RNA (shRNA) into PKD model mice reduced cyst growth and development by improving renal function [69▪▪]. In addition, the cystic area that originated from different nephron segments significantly decreased in size, which was associated with the downregulation of the RAGE gene. These observations suggest that the interaction of S100A8 and S100A9 with RAGE might play a role in the inflammatory reactions and progressive cystogenesis in ADPKD [69▪▪]. However, the precise mechanisms underlying the pathophysiological effects of RAGE on cyst growth and development are still unclear; therefore, further basic and clinical research is necessary to clarify this issue in the future.
RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS AND ACUTE KIDNEY INJURY IN SEPSIS
AKI is characterized by a rapid loss of kidney function caused by decreased renal blood flow, obstruction of the outflow tract, or damage to the renal filtration system in the kidney . Sepsis, a microbial infection syndrome complicated by systemic severe inflammation, is associated with the development of AKI . Although histological findings in septic AKI seemed to be normal under light microscopic examination, electron microscopic analysis revealed acute tubular injury with dilated lysosome and mitochondria .
Recently, Brodska et al. have demonstrated that increased soluble form of RAGE (sRAGE) in plasma is associated with 28-day mortality in patients with sepsis and is superior to procalcitonin, C-reactive protein, and lactate. Further, sRAGE is correlated with sepsis severity and individual organ failure . Therefore, sRAGE could be used as an early biomarker in the prognostication of the outcome in septic patients. Experimental abdominal sepsis induced by cecal ligation and puncture showed the sustained elevation of HMGB-1 in the circulation . Further, administration of sRAGE, a decoy receptor for RAGE ligands, or deletion of the RAGE gene, significantly improved the survival rate in mice in an experimental septic model . Yamamoto et al. demonstrated that several pathogen-derived LPS could bind to RAGE V-domain, and as a result induce NF-κB activation and TNF-α secretion in the LPS-associated septic shock model. Therefore, enhanced binding of HMGB-1 or LPS to RAGE might cause tubular injury and AKI in sepsis.
From the evidence presented here, it is obvious that the interaction of several RAGE ligands with RAGE play a role in a broad range of progressive kidney diseases such as diabetic nephropathy, hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, amyloidosis, ADPKD, and septic AKI (Fig. 1). Blockade of the various RAGE ligands–RAGE interactions might be a novel therapeutic strategy for preventing the development and progression of numerous progressive kidney diseases.
Financial support and sponsorship
This work was supported, in part, by the Grants-in-Aid for Welfare and Scientific Research (C; no. 22590904 to K.F.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Conflicts of interest
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