Ryotaro Ando

Publications (7)21.92 Total impact

• 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
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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; · 8.29 Impact Factor
• Article: Evidence for a positive association between serum carnitine and free testosterone levels in uremic men with hemodialysis.

  Kazuko Sakai, Kei Fukami, Sho-Ichi Yamagishi, Yusuke Kaida, Takeki Adachi, Ryotaro Ando, Rie Manabe, Aki Otsuka, Kenzo Sugi, Seiji Ueda, Seiya Okuda
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  ABSTRACT: Background and Aims: Low free testosterone levels are associated with sexual dysfunction and an increased risk of cardiovascular disease in male hemodialysis patients. Carnitine deficiency is frequently observed in hemodialysis patients as well. However, relationship between carnitine and testosterone levels remains unknown. In this study, we examined whether carnitine deficiency was independently associated with low free testosterone levels in male hemodialysis patients. Methods: Nineteen male hemodialysis patients underwent determinations of blood chemistries, including serum levels of free testosterone, carnitine and pentosidine, one of the well-characterized advanced glycation end products. Results: Mean free testosterone levels in hemodialysis patients were significantly lower than those in healthy controls (4.67 ± 2.69 vs 9.50 ± 3.67 pg/ml, p<0.001). Univariate analysis revealed that carnitine (p=0.023), pentosidine (inversely, p=0.027), blood glucose (inversely, p=0.032), creatinine (p=0.026) levels and statin use (inversely, p=0.034) were correlated with free testosterone values. Multiple stepwise regression analysis revealed that carnitine (p=0.001) and statin use (inversely, p=0.002) were the independent determinants of age-adjusted free testosterone levels in hemodialysis patients (r2=0.612). Conclusions: The present study gives the first evidence that decreased carnitine levels were independently associated with low free testosterone values in male hemodialysis patients. Our study suggests that decreased carnitine levels may be a novel therapeutic target for uremic men with hemodialysis.
  Rejuvenation Research 03/2013; · 3.83 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
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  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: Decreased serum carnitine is independently correlated with increased tissue accumulation levels of advanced glycation end products in hemodialysis patients.

  Takeki Adachi, Kei Fukami, Sho-Ichi Yamagishi, Yusuke Kaida, Ryotaro Ando, Kazuko Sakai, Hisashi Adachi, Aki Otsuka, Seiji Ueda, Kenzo Sugi, Seiya Okuda
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  ABSTRACT: SUMMARY AT A GLANCE: This study demonstrated decreased serum carnitine levels and elevated skin AGEs in hemodialysis patients, and provides a possible novel marker of cardiovascular outcomes in this group of patients. ABSTRACT: Background and Aims:   There is accumulating evidence that advanced glycation end products (AGEs) play a role in cardiovascular disease (CVD) in patients with hemodialysis (HD). Carnitine deficiency is frequently observed in HD patients, which may also contribute to CVD. In this study, we examined whether carnitine deficiency was independently associated with increased tissue accumulation levels of AGEs in HD patients. Methods:   One hundred twenty nine HD patients underwent determinations of blood chemistries including serum level of carnitine. Tissue AGE levels were evaluated by measuring skin autofluorescence with an AGE-reader. Results:   Serum carnitine levels were significantly lower, while skin AGE levels were significantly higher in HD patients compared with healthy control (p<0.001). In univariate analysis, β(2) -microglobulin (β(2) -MG) and carnitine (inversely) were correlated with skin AGE levels. Multiple stepwise regression analysis revealed that carnitine levels were one of the independent determinants of skin AGE levels (p=0.024). When β(2) -MG-adjusted skin AGE levels were stratified by serum carnitine levels, a statistical significance and dose-response relationship were observed (p=0.043). Furthermore, skin AGE levels were one of the independent determinants of serum carnitine levels as well (p=0.012). Conclusions:   The present study demonstrated that decreased carnitine levels were independently associated with increased skin AGE levels in HD patients. Since carnitine is reported to inhibit the formation of AGEs in vitro, our study suggests that supplementation of carnitine may be a therapeutic target for preventing the accumulation of tissue AGEs and subsequently reducing the risk of CVD in HD patients. © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.
  Nephrology 07/2012; · 1.31 Impact Factor
• Article: Proteinuria elevates asymmetric dimethylarginine levels via protein arginine methyltransferase-1 overexpression in a rat model of nephrotic syndrome.

  Yusuke Kaida, Seiji Ueda, Sho-Ichi Yamagishi, Yosuke Nakayama, Ryotaro Ando, Ryuji Iwatani, Kei Fukami, Seiya Okuda
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  ABSTRACT: Proteinuria is an independent risk factor for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction and is associated with proteinuria in CKD patients. Thus, ADMA can partially account for the increased risk of CVD in CKD patients presenting proteinuria. However, a causal relationship between proteinuria and ADMA remains to be demonstrated. We first investigated whether and how proteinuria might increase ADMA levels in adriamycin (ADR)-treated rats. Next, we examined the effects of human serum albumin (HSA) on ADMA production by human renal proximal tubular epithelial cells (RPTECs) cultured in vitro. Proteinuria was associated with ADMA levels in ADR treated rats. Although ADR treatment did not affect the expression levels of the dimethylarginine dimethylaminohydrolase (DDAH)-1 or -2 enzymes that degrade ADMA, it significantly increased the expression levels of protein arginine methyltransferase-1 (PRMT-1) that facilitates the production of ADMA. HSA increased the generation of reactive oxygen species in RPTECs, which was blocked by the anti-oxidant N-acetylcysteine (NAC) or an inhibitor of NADPH oxidase. Furthermore, HSA increased ADMA generation by RPTECs in a dose- and time-dependent manner and induced gene expression of PRMT-1 but not DDAHs, which were also suppressed by NAC. Our data suggest that proteinuria might enhance ADMA generation in tubular cells, at least in part via the overexpression of PRMT-1 triggered by oxidative stress. Our findings thereby propose a mechanistic link between proteinuria and ADMA levels in CKD patients.
  Life sciences 06/2012; 91(9-10):301-5. · 2.56 Impact Factor
• Article: Association of asymmetric dimethylarginine with severity of kidney injury and decline in kidney function in IgA nephropathy.

  Ayako Fujimi-Hayashida, Seiji Ueda, Sho-Ichi Yamagishi, Yusuke Kaida, Ryotaro Ando, Yosuke Nakayama, Kei Fukami, Seiya Okuda
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  ABSTRACT: Asymmetric dimethylarginine (ADMA) plays important roles in the pathogenesis of chronic kidney disease (CKD). We have recently found that ADMA is involved in glomerular sclerosis and tubulointerstitial fibrosis in an animal model of CKD. However, relationship between plasma ADMA levels and severity of renal damage in CKD patients remains unknown. Relatively young 109 biopsy-proven IgA nephropathy (IgAN) patients (age: 32.7 ± 13.2; estimated glomerular filtration rate, eGFR: 86.5 ± 28.8 ml/min/1.73 m²) were enrolled. We retrospectively investigated whether plasma levels of ADMA were associated with severity of the renal tissue damage and could be a predictor of the disease progression in our subjects. ADMA levels were higher in IgAN patients than age-, sex- and mean eGFR-matched healthy volunteers (0.53 ± 0.14 vs. 0.43 ± 0.08 μM, p < 0.01). ADMA levels were associated with the severity of glomerular and tubulointerstitial injury. Multiple stepwise regression analysis revealed that ADMA, but not proteinuria was an independent determinant for the disease progression assessed by annual reduction rates of eGFR. In univariate analyses, ADMA levels were correlated with proteinuria, total cholesterol, triglycerides, and uric acid. Proteinuria was a sole independent correlate of ADMA in multiple stepwise regression analysis. The present study demonstrated that ADMA was correlated with the severity of the renal tissue damage and could be a predictor of disease progression in IgAN patients.
  American Journal of Nephrology 01/2011; 33(1):1-6. · 2.54 Impact Factor
• Article: [Case of acute kidney injury related to intravenous zoledronic acid in a patient with multiple myeloma].

  Kiyomi Koike, Kei Fukami, Satoshi Morishige, Takuma Hazama, Kensei Taguchi, Ryotaro Ando, Makio Nagano, Junko Yoshimura, Seiji Ueda, Michitoshi Hashiguchi, Kiyoshi Tamaki, Hidemi Nishida, Seiya Okuda
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  ABSTRACT: We report the first case of acute kidney injury related to intravenous zoledronic acid (ZA)in a patient with multiple myeloma in Japan. A 37-year-old male was diagnosed as having multiple myeloma (MM) of the Bence Jones lambda type. He showed a good response to two courses of vincristine, adriamycin and dexamethasone (VAD) therapy, and remarkable reduction was seen in plasma cells in bone marrow from 38.4% to 6.8% and 24-hour urine protein from 18.5 g/dL to 2.8 g/dL. At that time, serum Cr(s-Cr) of 0.7 mg/dL and calcium of 9.3 mg/dL were in the normal range. ZA was administered intravenously at the dose of 4 mg for the first time. Subsequently, he developed a fever of up to 39.4 degrees C and used NSAIDs and cefepime. Four days later, s-Cr increasd rapidly to 7.3 mg/ dL and he received hemodialysis (HD) therapy. Four weeks later, renal biopsy was performed and demonstrated cast nephropathy (CN) and acute tubular necrosis. Seven months later, renal function had improved. ZA may be an identifiable precipitating factor of CN. We recommend that ZA should be used with caution, especially hypovolemia and NSAIDs, in patients with MM and renal insufficiency.
  Nippon Jinzo Gakkai shi 02/2009; 51(5):557-62.