Seiya Okuda

Kurume University, Куруме, Fukuoka, Japan

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Publications (208)799.81 Total impact

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    ABSTRACT: Receptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily, which binds not only to advanced glycation endproducts, but also to high-mobility group box-1, S100/calgranulins, amyloid fibrils, and lipopolysaccharide. We discuss the pathophysiological role of RAGE in both diabetic and nondiabetic progressive renal diseases, and its potential use for therapeutic interventions in these devastating disorders. Although initial studies about RAGE focused on diabetic nephropathy, a number of recent findings have revealed that RAGE also actively participates in the pathogenesis of nondiabetic progressive renal diseases, including hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, autosomal dominant polycystic kidney disease, renal amyloidosis, and septic acute kidney injury. Furthermore, blocking the RAGE by a neutralizing antibody or genetic deletion of RAGE was found to prevent the development and progression of various renal disorders. The interaction of several RAGE ligands with RAGE plays a role in a broad range of progressive kidney diseases. The 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.
    Current opinion in nephrology and hypertension. 01/2015; 24(1):54-60.
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    ABSTRACT: Advanced glycation endproducts (AGEs) and their receptor (RAGE) play a role in vascular complications in diabetes. We have previously shown that 17β-estradiol at 10 nmol/l, a nearly identical plasma concentration to that during mid-pregnancy, up-regulates RAGE expression in endothelial cells. The finding might suggest the involvement of 17β-estradiol in the deterioration of vascular complications in diabetes during pregnancy. However, the effects of the selective estrogen receptor modulator, bazedoxifene, on oxidative and inflammatory reactions in AGEs-exposed endothelial cells remain unknown. In this study, we addressed the issue. Ten nmol/l 17β-estradiol increased RAGE and monocyte chemoattractant protein-1 (MCP-1) gene and protein expression in human umbilical vein endothelial cells (HUVECs), both of which were blocked by 10 nmol/l bazedoxifene. Bazedoxifene at 10 nmol/l also significantly inhibited the AGEs-induced superoxide generation, RAGE and MCP-1 gene and protein expression in HUVECs. The present study suggests that blockade of the AGEs–RAGE axis by bazedoxifene might be a novel therapeutic target for preventing vascular damage in diabetes, especially in postmenopausal women.
    Climacteric 10/2014; · 1.96 Impact Factor
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    ABSTRACT: There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010.
    Clinical and Experimental Nephrology 09/2014; · 1.25 Impact Factor
  • International journal of cardiology. 08/2014;
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    ABSTRACT: Advanced glycation end products (AGEs) decrease adiponectin expression and suppress insulin signaling in cultured adipocytes through the interaction with a receptor for AGEs (RAGE) via oxidative stress generation. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. This study examined the effects of AGE-aptamer on adipocyte remodeling, AGE-RAGE-oxidative stress axis, and adiponectin expression in fructose-fed rats. Although AGE-aptamer treatment by an osmotic mini pump for 8 weeks did not affect serum insulin levels, it significantly decreased average fasting blood glucose and had a tendency to inhibit body weight gain in fructose-fed rats. Furthermore, AGE-aptamer significantly suppressed the increase in adipocyte size and prevented the elevation in AGEs, RAGE, and an oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG), levels in adipose tissues of fructose-fed rats at 14-week-old, while it restored the decrease in adiponectin mRNA levels. Our present study suggests that AGE-aptamer could improve glycemic control and prevent adipocyte remodeling in fructose-fed rats partly by suppressing the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for fructose-induced metabolic derangements.
    08/2014;
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    ABSTRACT: Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34(+) cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte-colony stimulating factor (G-CSF)-mobilized PB-CD34(+) cells in patients with decompensated liver cirrhosis. PB-CD34(+) cells were isolated from G-CSF-mobilized apheresis products. Ten patients were treated with G-CSF-mobilized PB-CD34(+) cells (treatment group) and 7 patients were treated with standard medical therapy. For mobilization, patients in the treatment group received subcutaneous injections of 10 μg G-CSF /kg/day for 5 days. The cells were then injected at three different doses (5×10(5) , 1×10(6) and 2×10(6) cells/kg) through the hepatic artery. Thereafter, all patients were followed-up for 24 months. G-CSF treatment and leukapheresis were well tolerated and no serious adverse events were observed. Patients in the treatment group had a significant but transient splenomegaly. After 24 weeks, serum albumin was significantly increased in patients who had received middle- or high-doses of CD34(+) cells compared to baseline. Doppler-US showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34(+) cell therapy. The hepatic vein pressure gradient decreased in 2 patients who received high-dose CD34(+) cells at week 16. CD34(+) cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.
    Journal of Gastroenterology and Hepatology 04/2014; · 3.33 Impact Factor
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    ABSTRACT: Abstract Late-onset hypogonadism (LOH) and depression contribute to cardiovascular disease (CVD) in male hemodialysis (HD) patients. Carnitine deficiency is frequently observed in HD patients, playing a role in CVD. We examined whether carnitine deficiency was independently associated with LOH and depression in these patients. Twenty-six male HD patients underwent determinations of serum levels of free carnitine and testosterone. Status of LOH and depression were evaluated by questionnaires using aging male symptoms' (AMS) scale and self-rating depression scale (SDS), respectively. Free carnitine and testosterone levels in male HD patients were significantly lower than those in age-matched healthy male subjects. Linear regression analysis showed that AMS scale was positively associated with SDS. Univariate regression analysis revealed that total carnitine (inversely), free carnitine (inversely) and HD duration were correlated with AMS scale. Multiple stepwise regression analysis revealed that free carnitine was an independent determinant of AMS scale. Furthermore, free carnitine was also independently correlated with SDS in male HD patients. This study demonstrated that decreased free carnitine levels were independently associated with AMS scale and SDS in male HD patients. The observations suggest that decreased free carnitine levels could be a marker and therapeutic target of LOH and depression in uremic men with HD.
    The Aging Male 03/2014; · 1.71 Impact Factor
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    Yosuke Nakayama, Seiji Ueda, Seiya Okuda
    Circulation Journal 02/2014; · 3.58 Impact Factor
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    ABSTRACT: The patient was a 48-year-old man hospitalized for jaundice and anemia after a 6-day history of diarrhea. Examination demonstrated hemolytic anemia, renal dysfunction, and thrombocytopenia. Typical hemolytic uremic syndrome (HUS) was suspected based on the preceding colitis; however, plasma exchange (PE) was performed because the possibility of atypical HUS (aHUS) could not be ignored, given that the patient was an adult male. After 4 days of PE, his laboratory results improved. Stool culture on admission yielded negative results for Escherichia coli serotype O157 and ADAMTS13 activity. Antinuclear antibodies were normal, and no other drugs or infections indicating HUS were detected. Four months after onset, he suffered recurrence of aHUS after colitis. As a result, aHUS was suspected and therefore, PE was performed on the day of hospitalization. We diagnosed aHUS due to a result indicating complement dysregulation on hemolytic assay testing, which detected a complement factor H abnormality. After undergoing PE and maintaining a stable condition, the interval between PEs was extended; however, on day 17 after the last PE, he suffered a recurrent aHUS attack again. He could not be weaned from PE and started showing an allergic reaction to PE treatment, thereby leading to a switch from PE to eculizumab. Since switching to eculizumab treatment, the patient has not experienced another aHUS attack and his condition remains stable.
    Nihon Jinzo Gakkai shi. 01/2014; 56(5):606-11.
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    ABSTRACT: 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).
    Diabetology and Metabolic Syndrome 01/2014; 6(1):86. · 1.92 Impact Factor
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    ABSTRACT: Oxidative stress and smoking contribute to endothelial dysfunction. Iron might also play a role in oxidative stress generation and endothelial dysfunction. However, the involvement of iron in smoking-induced endothelial dysfunction in healthy smokers remains unclear. Therefore, we examined here whether (1) intravenous iron infusion impaired endothelial function evaluated by flow-mediated vasodilatation (FMD) in non-smokers, and (2) deferoxamine, a potent iron chelator, ameliorated endothelial dysfunction in healthy smokers. Eight healthy young male non-smokers (23±4 years old) received intravenous injection of saccharated ferric oxide (0.7 mg/kg body weight), while 10 age-matched healthy male smokers received deferoxamine mesylate (8.3 mg/kg body weight). At baseline, 5 and 20 minutes after treatment with iron or deferoxamine, biochemical variables were measured, including serum iron and marondialdehyde (MDA), a marker of lipid oxidation, and endothelial function was simultaneously evaluated by FMD. Compared with non-smokers, FMD was significantly lower in smokers. Iron and MDA levels were significantly increased, whereas FMD was impaired by iron infusion in non-smokers. Conversely, deferoxamine treatment significantly decreased iron and MDA levels and restored the decreased FMD in smokers. Baseline serum iron and MDA levels in all 18 subjects (non-smokers and smokers) were correlated with each other. There was a significant inverse correlation between the changes in MDA values and FMD from baseline in 18 men. Endothelium-independent vasodilation by glyceryl trinitrate was unaltered by either treatment. Our present study suggests that iron-evoked oxidative stress might play a role in endothelial dysfunction in healthy smokers.
    PLoS ONE 01/2014; 9(2):e89433. · 3.53 Impact Factor
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    ABSTRACT: Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis (PD) therapy in end stage renal disease (ESRD) patients. We have found that pigment epithelium-derived factor (PEDF) has anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor (VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty-seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate (P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels (P < 0.001). In multiple stepwise regression analysis, age (P = 0.002) and dialysate VEGF levels (P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤3.31 g/dL) and low hemoglobin (≤11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 (P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients.
    Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 11/2013; · 1.53 Impact Factor
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    ABSTRACT: Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-β and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.
    Clinical Immunology 11/2013; 150(1):78-87. · 3.77 Impact Factor
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    ABSTRACT: Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury-induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.Kidney International advance online publication, 9 October 2013; doi:10.1038/ki.2013.398.
    Kidney International 10/2013; · 8.52 Impact Factor
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    ABSTRACT: Background and Aims: Advanced glycation end products (AGEs) contribute to cardiovascular disease in patients with hemodialysis. We have recently found that carnitine levels are inversely associated with skin AGE levels in hemodialysis patients. We examined whether L-carnitine supplementation reduced skin AGE levels in hemodialysis patients with carnitine deficiency. Methods: This has been a single-center study. One hundred and two hemodialysis patients (total carnitine levels <50 μmol/l) were enrolled and randomized to either oral administration of L-carnitine (900 mg/day) (N=51) or control (N=51). After 6 months, metabolic and inflammatory variables, including serum levels of carnitine were measured. Skin AGE levels were determined by evaluating skin autofluorescence with an AGE-reader. Results: There were no significant differences of clinical variables at baseline between the control and L-carnitine therapy group. Thirty-two patients did not complete the assessment or treatment of the study. Oral L-carnitine supplementation for 6 months significantly increased LDL-cholesterol, triglycerides, total, free and acyl carnitine levels, while it decreased alanine transaminase, acyl/free carnitine ratio, β2-microglobulin and skin AGE values. Change in total carnitine values from baseline (∆total carnitine) and ∆free carnitine were inversely associated with ∆skin AGE levels in L-carnitine-treated patients (p=0.036 and p=0.016, respectively). In multiple regression analysis, ∆free carnitine was a sole independent determinant of ∆skin AGEs (R2=0.178). Conclusions: The present study demonstrated that oral L-carnitine supplementation significantly decreased skin AGE levels in hemodialysis patients with carnitine deficiency. These observations suggest that supplementation of L-carnitine might be a novel therapeutic strategy for preventing the accumulation of tissue AGEs in carnitine-deficient patients with hemodialysis.
    Rejuvenation Research 08/2013; · 2.92 Impact Factor
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    ABSTRACT: Cardiorenal syndrome (CRS) is a condition in which a complex interrelationship between cardiovascular disease (CVD) and chronic kidney disease (CKD). Impairment of one organ could accelerate pathological processes in the other, which in turn accelerates the progression of failure of both. Although clinical studies hint at a specific bidirectional interaction between cardiovascular system and kidney, insight into the pathogenesis of CRS remains unknown. One possible factor that could explain this link is endothelial dysfunction (ED). ED is not only involved in initiation and progression of atherosclerosis, but also contributes to progression of renal injury. Asymmetric dimethylarginine (ADMA) is an endogenous NO synthase inhibitor found in the plasma and cells. Plasma ADMA levels are increased in CKD patients and known to be an independent biomarker and predictor for future cardiovascular events as well as the progression of CKD. These findings indicate that accumulated ADMA-mediated ED may play important roles in CRS in CKD patients. In this review, we discuss the roles of ADMA in the development of ED, especially focusing on its roles in CRS.
    Current pharmaceutical design 06/2013; · 4.41 Impact Factor
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    ABSTRACT: Advanced glycation end products (AGEs) are a heterogenous group of molecules formed during a non-enzymatic reaction between proteins and sugar residues. Recently, AGEs and their receptor (receptor for AGEs; RAGE) play a central role in the pathogenesis of cardiovascular disease (CVD), which accounts for disability and high mortality rate in patients with diabetes. AGEs initiate diabetic micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins as well as intracellular signaling molecules. Engagement of RAGEs with AGEs elicits intracellular reactive oxygen species (ROS) generation and subsequently activates mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-?B) signaling, followed by production of several inflammatory and/or profibrotic factors such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1), thereby being involved in the progression of atherosclerosis. Administration of soluble form of RAGE (sRAGE) could work as a decoy receptor for AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal models. Furthermore, AGEs/high mobility group box-1 (HMGB-1)-RAGE interaction is involved in heart failure, abdominal aortic aneurysm (AAA) and vascular calcification as well. Thus, blockade of the AGEs/HMBG-1-RAGE system may be a promising therapeutic target for preventing diabetes- and/or age-related CVD. We review here the pathological role of the AGEs/HMBG-1-RAGE system in various types of CVD.
    Current pharmaceutical design 06/2013; · 4.41 Impact Factor
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    ABSTRACT: Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, plays a role in endothelial dysfunction, an initial step of atherosclerosis. Advanced glycation end products (AGEs) also contribute to accelerated atherosclerosis. However, a pathophysiological crosstalk between ADMA and AGEs remains unclear. In this study, we investigated the relationship between ADMA and AGE level in patients with end-stage renal disease (ESRD) due to diabetic nephropathy. We also examined whether and how AGEs increased ADMA generation by cultured endothelial cells (ECs). Plasma ADMA levels were positively associated with serum AGE level and were inversely correlated with endothelial function determined by flow-mediated vasodilatation. AGEs dose dependently increased reactive oxygen species (ROS) generation in ECs, which was blocked by antisense DNA raised against receptor for AGEs (RAGE). Furthermore, AGEs decreased messenger RNA (mRNA) level of dimethylarginine dimethylaminohydrolase (DDAH)-II, an enzyme for ADMA degradation, reduced its total enzymatic activity and resultantly increased ADMA, all of which were completely blocked by an antioxidant, N-acetylcysteine. These results suggest that the AGE-RAGE-mediated ROS generation could be involved in endothelial dysfunction in diabetic ESRD patients partly by increasing the ADMA generation via suppression of DDAH activity in ECs.
    Diabetes & Vascular Disease Research 06/2013; · 2.59 Impact Factor
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    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; · 2.93 Impact Factor
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    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; · 7.90 Impact Factor

Publication Stats

3k Citations
799.81 Total Impact Points

Institutions

  • 1997–2014
    • Kurume University
      • • Division of Nephrology
      • • School of Medicine
      • • Department of Immunology
      • • Department of Internal Medicine
      • • Department of Pathology
      • • Cardiovascular Research Institute
      Куруме, Fukuoka, Japan
  • 2009
    • Shinmatsudo Central General Hospital
      Matsudo, Chiba, Japan
  • 1988–2008
    • Kyushu University
      • • Faculty of Medical Sciences
      • • Department of Clinical Medicine
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2005
    • IIzuka Hospital
      Иидзука, Fukuoka, Japan
  • 2002–2005
    • Kyushu Medical Center
      Hukuoka, Fukuoka, Japan
  • 2001
    • The Cardiovascular Institute
      Tōkyō, Japan
  • 1999
    • Stanford University
      • Falk Cardiovascular Research Center
      Palo Alto, CA, United States