Takanori Matsui

Publications (113)399.7 Total impact

• Article: Telmisartan inhibits AGE-induced podocyte damage and detachment.

  Kei Fukami, Sho-Ichi Yamagishi, Kumiko Kaifu, Takanori Matsui, Yusuke Kaida, Seiji Ueda, Masayoshi Takeuchi, Katsuhiko Asanuma, Seiya Okuda
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGE) formed at an accelerated rate under diabetes, could cause podocyte apoptosis, thereby being involved in the development and progression of diabetic nephropathy. Renin-angiotensin system (RAS) plays a role in diabetic nephropathy as well. However, it remains unknown whether there exists a pathophysiological crosstalk between the RAS and AGE in podocyte damage in diabetic nephropathy. Therefore, this study investigated the effects of telmisartan, an angiotensin II (Ang II) type 1 receptor (AT1R) blocker on AGE or Ang II-induced podocyte damage in vitro. We further examined here the effects of AGE on AT1R expression levels in podocytes. AGE or Ang II not only increased DNA damage of podocytes which was evaluated by comet assay, but also induced cell detachment, both of which were significantly blocked by the treatment with telmisartan. AGE significantly increased AT1R levels in podocytes, whereas podocyte Ang II production was modestly stimulated by AGE. Telmisartan alone did not affect the release of lactate dehydrogenase from podocytes. Our present study suggests that AGE could induce podocyte DNA damage and detachment partly via stimulation of the Ang II-AT1R axis, thus providing a novel beneficial aspect of telmisartan in diabetic nephropathy.
  Microvascular Research 05/2013; · 2.83 Impact Factor
• Article: DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy.

  Yusuke Kaida, Kei Fukami, Takanori Matsui, Yuichiro Higashimoto, Yuri Nishino, Nana Obara, Yosuke Nakayama, Ryotaro Ando, Maki Toyonaga, Seiji Ueda, Masayoshi Takeuchi, Hiroyoshi Inoue, Seiya Okuda, Sho-Ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro, and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2'-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor or type-IV collagen both in the kidney of KKAy/Ta mice and in AGEs-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy.
  Diabetes 04/2013; · 8.29 Impact Factor
• Article: Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products (AGEs)-induced tubular cell apoptosis.

  Sayaka Maeda, Takanori Matsui, Masayoshi Takeuchi, Sho-Ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUNDS: Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on the apical membrane of renal proximal tubules. Since blockade of SGLT2 promotes urinary glucose excretion and resultantly improves hyperglycemia, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. Moreover, advanced glycation end products (AGEs)-receptor (RAGE) system induces apoptosis of tubular cells, thereby playing a role in diabetic nephropathy as well. However, the pathophysiological crosstalk of SGLT2 with AGEs-RAGE axis and its role in diabetic nephropathy remains unknown. METHODS: This study investigated whether and how blockade of SGLT2 could prevent AGEs-elicited apoptosis of high glucose-exposed proximal tubular cells in vitro. RESULTS: SGLT2 was expressed in tubular cells. Tubular SGLT2 expression and glucose entry into the cells were completely blocked by the treatment with small interfering RNAs (siRNAs) raised against SGLT2. High glucose increased reactive oxygen species generation and RAGE expression levels in tubular cells, both of which were partly suppressed by SGLT2 siRNAs or an anti-oxidant, N-acetylcysteine. Further, high glucose was found to augment the AGEs-induced tubular cell apoptosis, which was also inhibited by SGLT2 siRNAs. CONCLUSIONS: Our present data suggest that SGLT2-mediated, high glucose-induced ROS generation could augment the AGEs-induced apoptotic cell death of tubular cells via RAGE induction. SGLT2 may play some role in tubular apoptosis in diabetic nephropathy. Copyright © 2013 John Wiley & Sons, Ltd.
  Diabetes/Metabolism Research and Reviews 03/2013; · 3.37 Impact Factor
• Article: Pigment epithelium-derived factor (PEDF) inhibits survival and proliferation of VEGF-exposed multiple myeloma cells through its anti-oxidative properties.

  Ritsuko Seki, Sho-Ichi Yamagishi, Takanori Matsui, Takafumi Yoshida, Takuji Torimura, Takato Ueno, Michio Sata, Takashi Okamura
  [show abstract] [hide abstract]
  ABSTRACT: Vascular endothelial growth factor (VEGF) has been reported not only to induce angiogenesis within the bone marrow, but also directly stimulate the proliferation and survival of multiple myeloma cells, thus being involved in the development and progression of this second most common hematological malignancy. We, along with others, have found that pigment epithelium-derived factor (PEDF) has anti-angiogenic and anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of VEGF. However, effects of PEDF on VEGF-exposed myeloma cells remain unknown. In this study, we examined whether and how PEDF could inhibit the VEGF-induced proliferation and survival of myeloma cells. PEDF, a glutathione peroxidase mimetic, ebselen, or an inhibitor of NADPH oxidase, diphenylene iodonium significantly inhibited the VEGF-induced reactive oxygen species (ROS) generation, increase in anti-apoptotic and growth-promoting factor, myeloid cell leukemia 1 (Mcl-1) expression, and proliferation in U266 myeloma cells. VEGF blocked apoptosis of multiple myeloma cells isolated from patients, which was prevented by PEDF. PEDF also reduced p22phox levels in VEGF-exposed U266 cells. Furthermore, overexpression of dominant-negative human Rac-1 mutant mimicked the effects of PEDF on ROS generation and Mcl-1 expression in U266 cells. Our present study suggests that PEDF could block the VEGF-induced proliferation and survival of multiple myeloma U266 cells through its anti-oxidative properties via suppression of p22phox, one of the membrane components of NADPH oxidase. Suppression of VEGF signaling by PEDF may be a novel therapeutic target for multiple myeloma.
  Biochemical and Biophysical Research Communications 01/2013; · 2.48 Impact Factor
• Article: Glucagon-like Peptide-1 Receptor Agonist Inhibits Asymmetric Dimethylarginine Generation in the Kidney of Streptozotocin-Induced Diabetic Rats by Blocking Advanced Glycation End Product-Induced Protein Arginine Methyltranferase-1 Expression.

  Ayako Ojima, Yuji Ishibashi, Takanori Matsui, Sayaka Maeda, Yuri Nishino, Masayoshi Takeuchi, Kei Fukami, Sho-Ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of RAGE, PRMT-1, ICAM-1, and MCP-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.
  American Journal Of Pathology 11/2012; · 4.89 Impact Factor
• Article: PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation.

  Yuji Ishibashi, Takanori Matsui, Keisuke Ohta, Ryuichiro Tanoue, Masayoshi Takeuchi, Katsuhiko Asanuma, Kei Fukami, Seiya Okuda, Kei-Ichiro Nakamura, Sho-Ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGEs) formed at an accelerated rate under diabetes, elicit oxidative and pro-apoptotic reactions in various types of cells, including podocytes, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited mesangial and tubular cell damage through its anti-oxidative properties. However, the effects of PEDF on podocyte loss, one of the characteristic features of diabetic nephropathy remain unknown. In this study, we investigated whether and how PEDF could protect against AGE-elicited podocyte apoptosis in vitro. AGEs decreased PEDF mRNA level in podocytes, which was blocked by neutralizing antibody raised against receptor for AGEs (RAGE-Ab). PEDF or RAGE-Ab was found to inhibit the AGE-induced up-regulation of RAGE mRNA level, oxidative stress generation and resultant apoptosis in podocytes. All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). Further, although PEDF did not affect protein expression levels of PPARγ, it significantly restored the PPARγ transcriptional activity in AGE-exposed podocytes. The present results demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARγ activation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for preventing the podocyte loss in diabetic nephropathy.
  Microvascular Research 10/2012; · 2.83 Impact Factor
• Article: Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice.

  Yoshimi Takamiya, Kei Fukami, Sho-Ichi Yamagishi, Yusuke Kaida, Yosuke Nakayama, Nana Obara, Ryuji Iwatani, Ryotaro Ando, Kiyomi Koike, Takanori Matsui, Yuri Nishino, Seiji Ueda, Mark E Cooper, Seiya Okuda
  [show abstract] [hide abstract]
  ABSTRACT: Background Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice.Methods Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone.ResultsCompared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-d-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice.Conclusions Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.
  Nephrology Dialysis Transplantation 09/2012; · 3.40 Impact Factor
• Article: Positive Association Between Serum Level of Glyceraldehyde-Derived Advanced Glycation End Products and Vascular Inflammation Evaluated by [18F]Fluorodeoxyglucose Positron Emission Tomography.

  Nobuhiro Tahara, Sho-Ichi Yamagishi, Masayoshi Takeuchi, Akihiro Honda, Atsuko Tahara, Yoshikazu Nitta, Norihiro Kodama, Minori Mizoguchi, Hayato Kaida, Masatoshi Ishibashi, Naofumi Hayabuchi, Takanori Matsui, Tsutomu Imaizumi
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE Advanced glycation end products (AGEs) evoke inflammatory reactions, contributing to the development and progression of atherosclerosis. We investigated the relationship between serum AGE level and vascular inflammation.RESEARCH DESIGN AND METHODS The study involved 275 outpatients at Kurume University, Japan (189 males and 86 females; mean age 61.2 ± 8.8 years) who underwent complete history and physical examinations and determinations of blood chemistry and anthropometric variables, including AGEs. Serum AGE level was examined by enzyme-linked immunosorbent assay. Vascular [(18)F]fluorodeoxyglucose (FDG) uptake, an index of vascular inflammation, was measured as blood-normalized standardized uptake value, known as the target-to-background ratio (TBR), by FDG-positron emission tomography (FDG-PET). Furthermore, we examined whether the changes in serum AGE level after treatment with oral hypoglycemia agents (OHAs) were correlated with those of TBR in another 18 subjects whose AGE value was >14.2 units/mL (mean ± 2 SD).RESULTSMean serum AGE level and carotid TBR values were 9.15 ± 2.53 and 1.43 ± 0.22 units/mL, respectively. Multiple stepwise regression analysis revealed that TBR was independently correlated with AGEs (P < 0.001), carotid intima-media thickness (P < 0.01), and BMI (P < 0.02). When age- and sex-adjusted AGE values stratified by TBR tertiles were compared using ANCOVA, a significant trend was observed (P < 0.01). In addition, the changes in AGEs after OHA treatment were positively (r = 0.50, P < 0.05) correlated with those in TBR value.CONCLUSIONS The current study reveals that serum AGE level is independently associated with vascular inflammation evaluated by FDG-PET, suggesting that circulating AGE value may be a biomarker that could reflect vascular inflammation within an area of atherosclerosis.
  Diabetes care 08/2012; · 8.09 Impact Factor
• Article: Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A.

  Yuji Ishibashi, Takanori Matsui, Ayako Ojima, Yuri Nishino, Sae Nakashima, Sayaka Maeda, Sho-Ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: There is a growing body of evidence that renin-angiotensin system plays a role in diabetic nephropathy. Recently, we have found that glucagon-like peptide-1 (GLP-1), one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake, inhibits advanced glycation end product-induced monocyte chemoattractant protein-1 gene expression in mesangial cells thorugh the interaction with the receptor of GLP-1. However, effects of GLP-1 on angiotensin II-exposed mesangial cells are unknown. This study investigated whether and how GLP-1 blocked the angiotensin II-induced mesangial cell damage in vitro. GLP-1 completely blocked the angiotensin II-induced superoxide generation, NF-κB activation, up-regulation of mRNA levels of intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 in mesangial cells, all of which were prevented by the treatments with H-89, an inhibitor of protein kinase A. The present results demonstrated for the first time that GLP-1 blocked the angiotensin II-induced mesangial cell injury by inhibiting superoxide-mediated NF-κB activation via protein kinase C pathway. Our present study suggests that strategies to enhance the biological actions of GLP-1 may be a promising strategy for the treatment of diabetic nephropathy.
  Microvascular Research 06/2012; · 2.83 Impact Factor
• Article: Serum pigment epithelium-derived factor levels are independently associated with decreased number of circulating endothelial progenitor cells in healthy non-smokers.

  Sho-Ichi Yamagishi, Sayaka Maeda, So Ueda, Yuji Ishibashi, Takanori Matsui
  International journal of cardiology 05/2012; 158(2):310-2. · 7.08 Impact Factor
• Article: Vildagliptin inhibits oxidative stress and vascular damage in streptozotocin-induced diabetic rats.

  Sayaka Maeda, Takanori Matsui, Sho-Ichi Yamagishi
  International journal of cardiology 05/2012; 158(1):171-3. · 7.08 Impact Factor
• Article: Pravastatin inhibits advanced glycation end products (AGEs)-induced proximal tubular cell apoptosis and injury by reducing receptor for AGEs (RAGE) level.

  Yuji Ishibashi, Sho-ichi Yamagishi, Takanori Matsui, Keisuke Ohta, Ryuichiro Tanoue, Masayoshi Takeuchi, Seiji Ueda, Kei-ichiro Nakamura, Seiya Okuda
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) axis play a role in diabetic nephropathy. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease. However, the effects of statin on AGEs-induced tubular cell damage remain unknown. We examined here whether and how pravastatin could block the AGEs-RAGE-elicited tubular cell injury in vitro. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. Reactive oxygen species (ROS) generation was measured with dihydroethidium staining. Apoptosis was analyzed in an enzyme-linked immunosorbent assay. Asymmetric dimethylarginine (ADMA) expression was evaluated by immunostaining. Pravastatin dose-dependently inhibited the AGEs-induced up-regulation of RAGE mRNA level, ROS generation and apoptosis in human renal proximal tubular cells. Further, AGEs decreased mRNA level of dimethylarginine dimethylaminohydrolase-2, an enzyme that mainly degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase and subsequently increased ADMA generation in tubular cells, both of which were also prevented by pravastatin. Geranylgeranyl pyrophosphate (GGPP) treatment blocked all of the effects of pravastatin on tubular cells. We found that rosuvastatin also significantly blocked the AGEs-induced increase in RAGE mRNA level and ROS generation, both of which were prevented by GGPP. Our present study suggests that pravastatin could inhibit the AGEs-induced apoptosis and ADMA generation in tubular cells by suppressing RAGE expression probably via inhibition of GGPP synthesis. Pravastatin may exert beneficial effects on tubular damage in diabetic nephropathy by blocking the AGEs-RAGE axis.
  Metabolism: clinical and experimental 03/2012; 61(8):1067-72. · 2.59 Impact Factor
• Article: PEDF-derived peptide inhibits corneal angiogenesis by suppressing VEGF expression.

  Takanori Matsui, Yuri Nishino, Sayaka Maeda, Sho-ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: Pigment epithelium-derived factor (PEDF) a glycoprotein that belongs to the superfamily of serine protease inhibitors, has been recently shown to be the most potent inhibitor of angiogenesis in the mammalian eye. However, which active domain of PEDF protein could be involved in its anti-angiogenic properties remains unknown. Therefore, in this study, we examined which PEDF-derived synthetic peptides could inhibit corneal neovascularization induced by chemical cauterization in vivo. Rats treated with topical application of PEDF protein had 31% less corneal neovascularization at day 7 after the injury than phosphate-buffered saline (PBS)-treated rats. P5-2 and P5-3 peptides (residues 388-393 and 394-400 of PEDF protein, respectively) significantly suppressed the corneal neovascularization after chemical cauterization at day 7, and its anti-angiogenic potential was almost equal to that of full-length PEDF protein. Further, full-length PEDF protein and P5-3 peptide significantly decreased 8-hydroxy-2'-deoxyguanosine and vascular endothelial growth factor (VEGF) levels in the corneal. Our present study suggests that PEDF-derived synthetic peptide, P5-3 could inhibit the corneal neovascularization induced by chemical cauterization in rats by suppressing VEGF expression via its anti-oxidative properties.
  Microvascular Research 02/2012; 84(1):105-8. · 2.83 Impact Factor
• Article: Serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects.

  Nobuhiro Tahara, Sho-Ichi Yamagishi, Takanori Matsui, Masayoshi Takeuchi, Yoshikazu Nitta, Norihiro Kodama, Minori Mizoguchi, Tsutomu Imaizumi
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans. Three hundred twenty-two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme-linked immunosorbent assay. Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low-density lipoprotein (LDL) cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C-reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age-adjusted HOMA-IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females. The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA-IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.
  Cardiovascular Therapeutics 02/2012; 30(1):42-8. · 2.35 Impact Factor
• Article: Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes.

  Sho-ichi Yamagishi, Takanori Matsui
  [show abstract] [hide abstract]
  ABSTRACT: Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathies, which could account for disabilities and high mortality rates in patients with diabetes. Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family. L cells in the small intestine secrete GLP-1 in response to food intake. GLP-1 not only enhances glucose-evoked insulin release from pancreatic β-cells, but also suppresses glucagon secretion from pancreatic α-cells. In addition, GLP-1 slows gastric emptying. Therefore, enhancement of GLP-1 secretion is a potential therapeutic target for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) is a responsible enzyme that mainly degrades GLP-1, and the half-life of circulating GLP-1 is very short. Recently, DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists have been developed and clinically used for the treatment of type 2 diabetes as a GLP-1-based medicine. GLP-1R is shown to exist in extra-pancreatic tissues such as vessels, kidney and heart, and could mediate the diverse biological actions of GLP-1 in a variety of tissues. So, in this paper, we review the pleiotropic effects of GLP-1-based therapies and its clinical utility in vascular complications in diabetes.
  Current pharmaceutical design 12/2011; 17(38):4379-85. · 4.41 Impact Factor
• Article: Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury.

  Yuji Ishibashi, Takanori Matsui, Masayoshi Takeuchi, Sho-ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-β mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation.
  Pharmacological Research 11/2011; 65(3):297-302. · 4.44 Impact Factor
• Article: Pigment epithelium-derived factor (PEDF) blocks advanced glycation end products (AGEs)-RAGE-induced suppression of adiponectin mRNA level in adipocytes by inhibiting NADPH oxidase-mediated oxidative stress generation.

  Sayaka Maeda, Takanori Matsui, Masayoshi Takeuchi, Sho-ichi Yamagishi
  International journal of cardiology 09/2011; 152(3):408-10. · 7.08 Impact Factor
• Article: Vardenafil, an inhibitor of phosphodiesterase-5, blocks advanced glycation end product (AGE)-induced up-regulation of monocyte chemoattractant protein-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression via elevation of cGMP.

  Yuji Ishibashi, Takanori Matsui, Masayoshi Takeuchi, Sho-ichi Yamagishi
  [show abstract] [hide abstract]
  ABSTRACT: Decreased production and/or impaired action of nitric oxide (NO) play a role in the pathogenesis of atherosclerotic cardiovascular disease and erectile dysfunction (ED) in diabetic patients. Under hyperglycemic conditions, formation and accumulation of advanced glycation end products (AGE) have been known to progress, thus contributing to tissue damage in diabetes. However, effects of inhibitors of phosphodiesterase-5 (PDE-5), an enzyme that catalyzes the degradation of cyclic guanosin-monophosphate (cGMP) and subsequently blocks the actions of NO, on AGE-exposed endothelial cells remain unknown. Therefore, this study investigated whether and how vardenafil, an inhibitor of PDE-5, could block the deleterious effects of AGE on human umbilical vein endothelial cells (HUVEC). Gene and protein expression was analyzed in quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and western blots, respectively. Intracellular formation of reactive oxygen species (ROS) was evaluated with dihydroethidium staining. AGE increased receptor for AGE (RAGE) mRNA and protein levels in HUVEC, both of which were significantly inhibited by the treatments with 30 nM vardenafil or 5 μM 8-Br-cGMP, an analogue of cGMP. Further, vardenafil reduced the AGE-induced ROS generation and subsequently inhibited up-regulation of monocyte chemoattractant protein-1 (MCP-1) mRNA levels in HUVEC. We demonstrated here for the first time that vardenafil could block the AGE-induced up-regulation of MCP-1 mRNA levels in HUVEC by suppressing RAGE expression and subsequent ROS generation via elevation of cGMP. Our present results suggest that vardenafil directly acts on endothelial cells and it could work as an anti-inflammatory agent against AGE.
  Clinical and Experimental Medicine 06/2011; 11(2):131-5. · 1.58 Impact Factor
• Article: Nitric oxide, a janus-faced therapeutic target for diabetic microangiopathy-Friend or foe?

  Sho-Ichi Yamagishi, Takanori Matsui
  [show abstract] [hide abstract]
  ABSTRACT: Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathy, which could account for disabilities and high mortality rates in patients with diabetes. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic vascular complications have now become one of the most challenging health problems. Nitric oxide (NO) is a pleiotropic molecule critical to a number of physiological and pathological processes in humans. NO not only inhibits the inflammatory-proliferative reactions in vascular wall cells, but also exerts anti-thrombogenic and endothelial cell protective properties, all of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes. However, high amounts of NO produced by inducible NO synthase (iNOS) and/or peroxynitrite (ONOO(-)), a reactive intermediate of NO with superoxide anion are involved in pro-inflammatory reactions and tissue damage as well. This implies that NO is a janus-faced molecule and acts as a double-edged sword in vascular complications in diabetes. Further, NO is synthesized from l-arginine via the action of NO synthase (NOS), while NOS is blocked by endogenous l-arginine analogues such as asymmetric dimethylarginine (ADMA), a naturally occurring amino acid which is found in the plasma and various tissues. These findings suggest that amounts of NO locally produced, oxidative stress conditions and level of ADMA could determine the beneficial and detrimental effects of NO on vascular complications in diabetes. In this paper, we review the janus-faced aspects of NO in diabetic microangiopathy.
  Pharmacological Research 05/2011; 64(3):187-94. · 4.44 Impact Factor
• Article: Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes.

  Sho-ichi Yamagishi, Sayaka Maeda, Takanori Matsui, Seiji Ueda, Kei Fukami, Seiya Okuda
  [show abstract] [hide abstract]
  ABSTRACT: A non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules, whose process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). In this paper, we review the role of AGE-oxidative stress axis and its therapeutic interventions in vascular complications in diabetes. AGEs elicit oxidative stress generation and subsequently cause inflammatory and thrombogenic reactions in various types of cells via interaction with a receptor for AGEs (RAGE), thereby being involved in vascular complications in diabetes. In addition, mitochondrial superoxide generation has been shown to play an important role in the formation and accumulation of AGEs under diabetic conditions. Further, we have recently found that a pathophysiological crosstalk between AGE-RAGE axis and renin-angiotensin system (RAS) could contribute to the progression of vascular damage in diabetes. These observations suggest that inhibition of AGE-RAGE-oxidative stress axis or blockade of its interaction with RAS is a novel therapeutic strategy for preventing vascular complications in diabetes.
  Biochimica et Biophysica Acta 03/2011; 1820(5):663-71. · 4.66 Impact Factor