Hitoshi Sugiyama

Okayama University, Okayama, Okayama, Japan

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Publications (112)370.54 Total impact

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    ABSTRACT: Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1+/-) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1+/- mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1+/- mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31+ endothelial area was also increased in the diabetic VASH1+/- mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1+/- mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.
    PLoS ONE 09/2014; 9(9):e107934. · 3.53 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; · 1.71 Impact Factor
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    ABSTRACT: Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r=0.48, p=0.001) or cortex (r=0.64, p<0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r=0.34, p=0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r=0.44, p=0.01) or medulla (r=0.63, p=0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2.
    Acta medica Okayama 08/2014; 68(4):219-41. · 0.75 Impact Factor
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    ABSTRACT: This study aimed to describe the influences of larger physical constitutions including obesity on the amount of urine protein excretion (AUPE) in primary glomerulonephritis. The distinct effects on the AUPE in various types of glomerulonephritis were evaluated.
    Clinical and Experimental Nephrology 06/2014; · 1.71 Impact Factor
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    ABSTRACT: Vasohibin-1 (VASH-1) is a negative feedback regulator of angiogenesis, and a small vasohibin-binding protein (SVBP) serves as its secretory chaperone and contributes to its antiangiogenic effects. In the present study, we aimed to define the clinical significance of VASH-1 and SVBP in patients with chronic kidney disease (CKD). We recruited 67 Japanese hospitalized patients with renal disorders with (n = 45) or without (n = 22) renal biopsy samples and 10 Japanese healthy controls. We evaluated the correlations between the plasma and urinary levels of VASH-1/VASH-1-SVBP complex/SVBP and the clinicopathological parameters. The plasma levels of VASH-1 were inversely correlated with age and systolic and diastolic blood pressure and positively correlated with crescent formation. Increased plasma and urinary levels of VASH-1 and VASH-1-SVBP complex were significantly correlated with worse renal outcomes. These results demonstrate an association between elevated urinary and plasma levels of VASH-1 and progressive decline of the renal function, thus suggesting a potential role for VASH-1 in predicting a worse renal prognosis in patients with renal disease, including CKD.
    PLoS ONE 06/2014; 9(6):e96932. · 3.53 Impact Factor
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    ABSTRACT: Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease (CKD). We recently reported the protective role of Vasohibin-1(VASH-1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH-1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin-1 heterozygous knockout mice (VASH-1+/−) or wild-type (WT) (VASH-1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys (OBK) were significantly exacerbated in VASH-1+/− mice compared with WT mice (Day 7). The increases in the renal levels of TGF-β1, pSmad3, NF-κB pp65, CCL2 mRNA, and the number of interstitial fibroblast-specific protein-1 (FSP-1)+ fibroblasts in the OBK were significantly aggravated in VASH-1+/− mice. In addition, treatment with VASH-1 siRNA enhanced the TGF-β1-induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH-1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti-fibrotic effects of VASH-1 on renal fibroblasts through its modulation of TGF-β1 signaling.
    Physiological Reports. 06/2014; 2(6).
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    ABSTRACT: A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.
    Acta medica Okayama 02/2014; 68(1):53-56. · 0.75 Impact Factor
  • Hiroshi Sato, Hitoshi Sugiyama, Hitoshi Yokoyama
    Nihon Jinzo Gakkai shi. 01/2014; 56(4):464-70.
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    ABSTRACT: Long-term peritoneal dialysis (PD) causes chronic peritoneal damage. Peritoneal mesothelial cells (PMCs) play an important role for peritoneal function. We investigated the possibility of cell therapy using the PMCs to prevent peritoneal damage in PD patients. We harvested human PMCs from the peritoneal dialysis effluent of PD patients. The PMCs were separated based on morphological characteristics into epithelial-like (Epi) cells and fibroblast-like (Fib) cells by the limiting dilution method. We transplanted these cells into nude mice whose parietal and visceral peritoneum were scratched by mechanical scraping. The transplanted cells were detected at the parietal and visceral peritoneum. Compared with the positive control, the Epi cell therapy group showed very few adhesions and exhibited no thickening of the parietal and visceral peritoneum. However, the group with Fib cell therapy could not inhibit peritoneal adhesion and thickening. In addition, HGF was expressed by the grafted Epi cells but not Fib cells. Fib cells expressed VEGF stronger than Epi cells. These two types of cells from same patient showed different character and effect for cell therapy. These findings suggest that the PMCs from the PD patient showed different character, such as Epi cells and Fib cells, and the selection of PMCs is important for cell therapy on the point of not only the direct cellular interactions but also cytokine secretion from the grafted cells. Furthermore, the differences in the morphological cell characteristics may influence their role in peritoneal regeneration.
    Tissue Engineering Part A 09/2013; · 4.64 Impact Factor
  • Nihon Naika Gakkai Zasshi 05/2013; 102(5):1083-91.
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    ABSTRACT: OBJECTIVES: Alloxan generate hydrogen peroxide in the body, and a small amount of alloxan administered to acatalasemic mice results in diabetes. D-α-Tocopherol (vitamin E) is an antioxidant which helps prevent excess oxidation in the body. In this study, we examined the effect of vitamin E on diabetes caused by alloxan administration in mice. METHODS: Mice were maintained on a vitamin E-deprived diet and supplemented diet, respectively, for 14weeks. Alloxan was then intraperitoneally administered, and blood glucose, glucose tolerance and the insulin level in mouse blood were examined. RESULTS: Hyperglycemia was observed in the mice maintained on the vitamin E-deprived diet. The incidence of hyperglycemia in the mice maintained on the vitamin E-deprived diet was significantly higher than that in the mice maintained on the supplemented diet. The abnormal glucose metabolism caused by alloxan administration was ameliorated by the vitamin E-supplemented diet. CONCLUSIONS: It is deduced that vitamin E can prevent a decrease of insulin concentration in the blood in this mouse model.
    Clinical biochemistry 03/2013; · 2.02 Impact Factor
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    ABSTRACT: The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.
    Clinical and Experimental Nephrology 02/2013; · 1.71 Impact Factor
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    ABSTRACT: Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD). We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification. The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075). Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.
    PLoS ONE 01/2013; 8(2):e56695. · 3.53 Impact Factor
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    ABSTRACT: Renal involvement with significant organ damage is common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). As a result, it is independently referred to ANCA-associated renal vasculitis. Clinically, ANCA-associated renal vasculitis is characterized by rapidly progressive glomerulonephritis. Pathologically, it is defined by pauci-immune type necrotizing and crescentic glomerulonephritis. According to previous reports from all over the world, the etiology, prevalence, and prognosis of RPGN including ANCA-associated renal vasculitis varies among races and periods. To elucidate the clinical characteristics of Japanese RPGN patients, a registry derived from a questionnaire survey was established in 1999 and maintained until 2006. As a result, 1,772 cases were collected, analyzed, and reported previously. In this mini-review, we outline the characteristic clinical findings of Japanese patients (Asian) with ANCA-associated renal vasculitis, based on the registry data.
    Clinical and Experimental Nephrology 12/2012; · 1.71 Impact Factor
  • Kidney International 11/2012; 82(9):1037. · 8.52 Impact Factor
  • Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 11/2012; 32(6):587-9.
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    ABSTRACT: BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.
    Clinical and Experimental Nephrology 10/2012; · 1.71 Impact Factor
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    ABSTRACT: Fabry disease (FD) is an Xlinked disorder resulting in a deficiency in α-galactosidase A (α-Gal) activity. FD is one of the causes of progressive renal dysfunction, but its diagnosis is often delayed or missed completely. We herein report the case of a 70-year-old male who had been receiving hemodialysis (HD) for 23 y who was diagnosed with FD after his participation in a screening program for plasma α-Gal activity for 892 HD patients. He had a low plasma α-Gal activity level and was demonstrated to have an E66Q mutation in exon 2 of the α-Gal gene. One of his daughters had the same mutation. The proband died due to aspiration pneumonia before receiving enzyme replacement therapy. We reviewed previous studies and found E66Q mutation in 36% of Japanese FD patients on HD including the present case. The clinical characteristics of E66Q variant are also discussed.
    Clinical nephrology 09/2012; 78(3):224-9. · 1.23 Impact Factor
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    ABSTRACT: Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia without a known predisposing cause. We report a 36-year-old man who had suffered membranoproliferative glomerulonephritis (MPGN) in his childhood, later diagnosed with CVID at 35 years of age. He presented at our hospital with signs of proteinuria. A renal biopsy revealed he suffered from focal segmental glomerulosclerosis (FSGS), possibly due to obesity and hypertension, not CVID - associated MPGN. This is the first case report of FSGS in a CVID patient. In this case, we have to pay attention not only to the treatment of obesity and hypertension for FSGS but also to the recurrence of immune-complex glomerulonephritis such as MPGN, in case of the restoration of hypogammaglobulinemia.
    BMC Nephrology 06/2012; 13:46. · 1.52 Impact Factor
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    ABSTRACT: Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model. ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups. The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation. These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.
    BMC Nephrology 03/2012; 13:14. · 1.52 Impact Factor

Publication Stats

2k Citations
370.54 Total Impact Points


  • 1995–2013
    • Okayama University
      • Department of Medicine and Clinical Science
      Okayama, Okayama, Japan
  • 2001–2012
    • University of Tsukuba
      • Department of Neurology
      Tsukuba, Ibaraki-ken, Japan
  • 2011
    • Minami Okayama Medical Center
      Okayama, Okayama, Japan
  • 2009
    • Chiba-East National Hospital
      Tiba, Chiba, Japan
  • 2003
    • Kawasaki Medical University
      • Department of General Internal Medicine 2
      Kurasiki, Okayama, Japan