Advanced glycation end products, oxidative stress and diabetic nephropathy

About 246 million people worldwide had diabetes in 2007. The global figure of people with diabetes is projected to increase to 370 million in 2030. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. In this paper, we review the pathophysiological role of AGEs and their receptor (RAGE)-oxidative stress system in diabetic nephropathy

Cancer Malignancy Is Enhanced by Glyceraldehyde-Derived Advanced Glycation End-Products

The receptor for advanced glycation end-products (RAGEs) is associated with the malignancy of cancer. A recent study has suggested that glyceraldehyde-derived AGEs (Glycer-AGEs) enhanced the malignancy of melanoma cells, but glucose-derived AGEs did not. However, the effects of Glycer-AGEs on other cancer cells remain poorly understood, and the molecular mechanisms behind the above-mentioned effect have not been clarified. The present paper aimed to examine the effect of Glycer-AGEs on cultured lung cancer A549 cells. RAGE was expressed in A549 cells. Glycer-AGEs significantly attenuated cell proliferation. Furthermore, Glycer-AGEs enhanced the migration capacity of the cells by activating Rac1 via ROS and also increased their invasion capacity. We demonstrated that Glycer-AGEs enhanced the migration and invasion of A549 cells rather than their proliferation. These results suggest that Glycer-AGEs play a critical role in the malignancy of cancer rather than its proliferation and are potential targets for therapeutic intervention

Involvement of TAGE-RAGE System in the Pathogenesis of Diabetic Retinopathy

Diabetic complications are a leading cause of acquired blindness, end-stage renal failure, and accelerated atherosclerosis, which are associated with the disabilities and high mortality rates seen in diabetic patients. Continuous hyperglycemia is involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including increased generation of various types of advanced glycation end-products (AGEs). Recently, we demonstrated that glyceraldehyde-derived AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, recent evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications. In this paper, we discuss the pathophysiological role of the TAGE-RAGE system in the development and progression of diabetic retinopathy

Insulin resistance is an independent correlate of high serum levels of advanced glycation end products (AGEs) and low testosterone in non-diabetic men

Advanced glycation end products (AGEs) are involved in cardiovascular disease. Low testosterone level is associated with increased risks of cardiometabolic disorders as well. However, which anthropometric and metabolic variables, including AGEs, are independently correlated with low testosterone is largely unknown. In this study, we investigated whether high serum level of AGEs is one of the independent determinants of low testosterone in non-diabetic men. One hundred thirteen non-diabetic men who did not receive any drugs for hypertension and dyslipidemia underwent a complete history and physical examination, determination of blood chemistries, including serum AGEs and testosterone. Univariate analysis showed that testosterone levels were associated with waist circumference (inversely), diastolic blood pressure (BP) (inversely), mean BP (inversely), triglycerides (inversely), HDL-cholesterol, fasting plasma glucose (inversely), fasting insulin (inversely), homeostasis model assessment of insulin resistance (HOMA-IR) (inversely), AGEs (inversely) and uric acid (inversely). By the use of multiple stepwise regression analyses, HOMA-IR (p = 0.005) and triglycerides levels (p < 0.05) remained significant and were independently related to testosterone levels (R2 = 0.168). HOMA-IR index was one of the independent determinants of serum levels of AGEs as well. The present study demonstrated for the first time that HOMA-IR was independently associated with high serum levels of AGEs and low testosterone in non-diabetic men. Insulin resistance could link elevation of AGEs to testosterone deficiency in non-diabetic men

後期糖化反応生成物による血管内皮細胞・周皮細胞傷害とその機構の解明

金沢大学医薬保健研究域医学系(1) ウシ血清アルブミン(bovine serum albumin、以下BSA)をグルコースと無菌的にインキュベートしてadvanced glycation endproducts化BSA(AGE-BSA)調製した。AGE-BSAは、内皮細胞表面に存在するAGE受容体(RAGE)との相互作用によりPAI-1産生を上昇させることが見い出された。このAGE効果はPGI_2アナログなどのサイクリックAMPアゴニストによってほぼ完全に抑制されることから、AGE-RAGE系の細胞内情報伝達系にサイクリックAMPが抑制的に作用することが推定された。(2) 内皮細胞に特異的なflk-1プロモーターの下流にヒトRAGE遺伝子を連結し、血管細胞でAGE受容体が過剰に発現するトランスジェニック(RAGE-Tg)マウスを作製した。(3) 遺伝的にインスリン依存性糖尿病を発症するマウスをこのRAGE-Tgマウスとかけあわせると、蛋白尿や糸球体硬化症の程度が増悪することが観察された。以上により、AGE-RAGE系は糖尿病性細小血管症の発症、進展に関与するものと考えられた。研究課題/領域番号:09770095, 研究期間(年度):1997 – 1998出典：「後期糖化反応生成物による血管内皮細胞・周皮細胞傷害とその機構の解明」研究成果報告書　課題番号09770095（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-09770095/)を加工して作

Association between plasma levels of pigment epithelium-derived factor and renal dysfunction in patients with coronary artery disease

Background: Although plasma pigment epithelium-derived factor (PEDF) levels have been shown to be significantly correlated with the levels of creatinine (Cr) in type 2 diabetes, little is known about the association between PEDF levels and renal dysfunction in patients with coronary artery disease (CAD). Methods: We enrolled 134 consecutive patients with diagnosed CAD and measured plasma levels of PEDF, serum Cr, uric acid (UA) and high-sensitive C-reactive protein (hsCRP). Results: Plasma PEDF levels were positively correlated with serum Cr (p < 0.0001) and UA (p < 0.0001) and negatively correlated with the estimated glomerular filtration rate (eGFR) (p < 0.0001), whereas there was no association between plasma PEDF and age or hsCRP. When the subjects were divided into five groups (0&#8211;4) according to the number of metabolic factors (obesity, diabetes, hypertension and dyslipidemia), PEDF levels in patients with four factors were significantly higher than those in patients without factors. Next, we divided the patients into quartiles according to their plasma PEDF levels (< 9.9 &#956;g/mL, 9.9&#8211;12.8, 12.9&#8211; &#8211;15.7, > 15.7). The eGFR in the first group was significantly higher than those in the third and fourth groups. Multivariate logistic analysis indicated that eGFR (p < 0.0001) and age (p = 0.030) were significant independent variables that correlated with the quartile classification according to PEDF levels. Conclusions: This study revealed that PEDF may play a role in renal dysfunction in CAD patients. (Cardiol J 2011; 18, 5: 515&#8211;520

Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy

Background: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs).Methods. Experimental diabetes was induced in 6-week-old male Sprague-Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10 M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB- phosphorylation inhibitor.Results: AGE and RAGE expression levels and MMP-2 activity in the tubules of diabetic rats was significantly increased in association with increased albuminuria, all of which were blocked by ramipril. AGE infusion induced tubular MMP-2 activation and RAGE gene expression in SD rats. Ramiprilat or BAY11-7082 inhibited the AGE-induced MMP-2 activation or reactive oxygen species generation in RPTCs. Angiotensin II increased MMP-2 gene expression in RPTCs, which was blocked by BAY11-7082.Conclusions: Our present study suggests the involvement of AGE-RAGE-induced, RAS-mediated MMP-2 activation in experimental DN. Blockade of AGE-RAGE axis by ramipril may protect against DN partly via suppression of MMP-2

AGEs activate mesangial TGF-β–Smad signaling via an angiotensin II type I receptor interaction

AGEs activate mesangial TGF-β–Smad signaling via an angiotensin II type I receptor interaction.BackgroundThe renin-angiotensin system (RAS) and the accumulation of advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic nephropathy. Whether there is a functional interaction between the RAS and AGEs in diabetic nephropathy is not known. In this study, we investigated whether AGEs could activate autocrine angiotensin II (Ang II) signaling and subsequently induce transforming growth factor-β (TGF-β)–Smad signaling in cultured rat mesangial cells.MethodsThe intracellular formation of reactive oxygen species (ROS) was detected using the fluorescent probe CM-H2DCFDA. Ang II was measured by radioimmunoassay. TGF-β released into media was quantitatively analyzed in an enzyme-linked immunosorbent assay (ELISA). Smad2, p27Kip1 (p27), fibronectin, and receptor for AGEs (RAGE) protein expression were determined by Western blot analysis. TGF-β–inducible promoter activity was analyzed by a luciferase assay. DNA synthesis was evaluated by 5-bomo-2′-deoxyuridine (BrdU) incorporation and de novo protein synthesis was determined by [3H]leucine incorporation.ResultsAGEs increased intracellular ROS generation in mesangial cells, and this effect was significantly inhibited by an antiserum against RAGE. AGEs also were found to stimulate Ang II production in a time- and dose-dependent manner, which was completely prevented by an antioxidant, N-acetylcysteine (NAC). AGE-induced TGF-β overproduction was completely blocked by candesartan, an Ang II type 1 receptor (AT1R) antagonist. Both candesartan and neutralizing antibody against TGF-β completely prevented AGEs-induced Smad2 phosphorylation and TGF-β–inducible promoter activity. Furthermore, AGEs were found to inhibit DNA synthesis and to stimulate de novo protein synthesis and fibronectin production in association with up-regulation of p27. All of these phenomena were completely prevented by candesartan or a polyclonal antibody against TGF-β.ConclusionThe present study suggests that AGE-RAGE–mediated ROS generation activates TGF-β–Smad signaling and subsequently induces mesangial cell hypertrophy and fibronectin synthesis by autocrine production of Ang II. This pathway may provide an important link between metabolic and haemodynamic factors in promoting the development and progression of diabetic nephropathy

Relationship between advanced glycation end products and plaque progression in patients with acute coronary syndrome: the JAPAN-ACS Sub-study.

Background: The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV.Methods: Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment > 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8-12 months after PCI.Results: At baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models.Conclusions: High baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS.Trial registration: NCT00242944. © 2013 Fukushima et al.; licensee BioMed Central Ltd