Ryotaro Ando

Kurume University, Куруме, Fukuoka, Japan

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Publications (11)36.2 Total impact

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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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    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; · 7.92 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: 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 (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
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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; · 2.92 Impact Factor
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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; · 3.37 Impact Factor
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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; · 1.69 Impact Factor
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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
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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. · 2.62 Impact Factor
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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.