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Masashi Kitagawa,
Hitoshi Sugiyama, Hiroshi Morinaga,
Tatsuyuki Inoue,
Keiichi Takiue,
Ayu Ogawa,
Toshio Yamanari,
Yoko Kikumoto,
Haruhito Adam Uchida,
Shinji Kitamura,
Yohei Maeshima,
Kazufumi Nakamura,
Hiroshi Ito,
Hirofumi Makino
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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. · 4.09 Impact Factor
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Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 11/2012; 32(6):587-9.
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Keiichi Takiue,
Hitoshi Sugiyama,
Tatsuyuki Inoue, Hiroshi Morinaga,
Yoko Kikumoto,
Masashi Kitagawa,
Shinji Kitamura,
Yohei Maeshima,
Da-Hong Wang,
Noriyoshi Masuoka,
Keiki Ogino,
Hirofumi Makino
[show abstract]
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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. · 2.18 Impact Factor
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Hiroshi Morinaga,
Hitoshi Sugiyama,
Tatsuyuki Inoue,
Keiichi Takiue,
Yoko Kikumoto,
Masashi Kitagawa,
Shigeru Akagi,
Kazushi Nakao,
Yohei Maeshima,
Ikuko Miyazaki,
Masato Asanuma,
Makoto Hiramatsu,
Hirofumi Makino
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ABSTRACT: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD.
Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months.
Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma β(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005).
Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients.
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 01/2012; 32(4):453-61.
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ABSTRACT: The pathogenesis of IgA nephropathy (IgAN) may be associated with the mesangial deposition of aberrantly glycosylated IgA1. To identify mediators affected by aberrantly glycosylated IgA1 in cultured human mesangial cells (HMCs), we generated enzymatically modified desialylated and degalactosylated (deSial/deGal) IgA1. The state of deglycosylated IgA1 was confirmed by lectin binding to Helix aspersa (HAA) and Sambucus nigra (SNA). In the cytokine array analysis, 52 proteins were upregulated and 34 were downregulated in HMCs after stimulation with deSial/deGal IgA1. Among them, the secretion of adiponectin was suppressed in HMCs after stimulation with deSial/deGal IgA1. HMCs expressed mRNAs for adiponectin and its type 1 receptor, but not the type 2 receptor. Moreover, we revealed a downregulation of adiponectin expression in the glomeruli of renal biopsy specimens from patients with IgAN compared to those with lupus nephritis. We also demonstrated that aberrantly glycosylated IgA1 was deposited in the mesangium of patients with IgAN by dual staining of HAA and IgA. Moreover, the urinary HAA/SNA ratio of lectin binding was significantly higher in IgAN compared to other kidney diseases. Since adiponectin has anti-inflammatory effects, including the inhibition of adhesion molecules and cytokines, these data suggest that the local suppression of this adipokine by aberrantly glycosylated IgA1 could be involved in the regulation of glomerular inflammation and sclerosis in IgAN.
PLoS ONE 01/2012; 7(3):e33965. · 4.09 Impact Factor
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[show abstract]
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ABSTRACT: There are still controversies whether peritoneal dialysis (PD) with icodextrin preserves residual renal and peritoneal membrane functions in patients with diabetes. However, there are no randomized controlled and long-term clinical trials in newly started PD patients with diabetic nephropathy.
Forty-one patients with diabetic nephropathy with ESRD were enrolled and randomly assigned to the glucose group (GLU) treated with 8 L of 1.5% or 2.5% glucose or an icodextrin group (ICO) treated with 1.5 or 2.0 L of 7.5% icodextrin-containing solutions. Technique failure, body fluid management, glucose and lipid metabolism, and residual renal and peritoneal functions and were evaluated over 2 years.
The technique survival rate was 71.4% in ICO and 45.0% in GLU, with most of the technique failure due to volume overload. ICO showed significantly better cumulative technique survival. Net ultrafiltration volume was significantly higher in ICO throughout the study period. There were no beneficial effects of icodextrin on hemoglobin A1c, glycoalbumin, and lipid profile at 24 months. Urine volume and residual renal function declined faster in ICO, but there were no significant differences between the two groups. For peritoneal function, no differences were observed in dialysis-to-plasma creatinine ratios during the observation.
In PD therapy for diabetic nephropathy, the use of icodextrin-containing solutions has a beneficial effect on technique survival, but there are no apparent benefits or disadvantages in residual renal and peritoneal functions compared with conventional PD with glucose solution.
Clinical Journal of the American Society of Nephrology 06/2011; 6(6):1337-44. · 5.23 Impact Factor
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Tatsuyuki Inoue,
Hitoshi Sugiyama,
Masashi Kitagawa,
Keiichi Takiue, Hiroshi Morinaga,
Yoko Kikumoto,
Yohei Maeshima,
Kunihiro Fukushima,
Kazunori Nishizaki,
Hirofumi Akagi,
Yoshiyuki Hiki,
Hirofumi Makino
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ABSTRACT: Glycosylation, which represents the most complex post-translational modification, plays a pivotal role during protein maturation, and is orchestrated by numerous glycosyltransferases. Aberrant O-glycosylation of serum and tonsillar IgA1 is presumed to be one of the pathogeneses of IgA nephropathy (IgAN). However, the synthesis of underglycosylated IgA1 in tonsils has not yet been characterized. This study investigated tonsillar B lymphocytes of IgAN using tonsils from patients with chronic tonsillitis and sleep apnea syndrome. Gene expression of β1,3-galactosyltransferase (β3GalT), Cosmc, UDP-N-acetyl-α-D-galactosamine: polypeptide N-acetylgalactosaminyl-transferase 2, were significantly down regulated in tonsillar CD19-positive B lymphocytes from IgAN patients compared to control as determined by real-time RT-PCR. In contrast, the level of sialyltransferase was not significantly different among the three groups. Tonsillar B cell β3GalT gene expression significantly correlated with estimated GFR and negatively correlated with proteinuria and glomerular or interstitial injury score. Double immunofluorescent staining showed that some IgA-positive cells in the intrafollicular area were also positive for β3GalT staining. Western blotting showed the protein expression of β3GalT in the tonsils to significantly decrease in IgAN in comparison to the controls. These data suggest the downregulation of β3GalT in tonsillar B lymphocytes to be closely associated with the clinical characteristics of IgAN.
Advances in Oto-Rhino-Laryngology 01/2011; 72:71-4.
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Masashi Kitagawa,
Hitoshi Sugiyama, Hiroshi Morinaga,
Tatsuyuki Inoue,
Keiichi Takiue,
Yoko Kikumoto,
Haruhito Adam Uchida,
Shinji Kitamura,
Yohei Maeshima,
Norihisa Toh,
Kazufumi Nakamura,
Hiroshi Ito,
Hirofumi Makino
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ABSTRACT: Chronic kidney disease (CKD) is associated with left-ventricular (LV) diastolic dysfunction (LVDD) which progresses to diastolic heart failure. However, biomarkers predicting LVDD in patients with CKD are largely unknown.
In 93 patients with non-diabetic CKD, the relationships among echocardiography, high-sensitivity cardiac troponin T (hs-cTnT), B-type natriuretic peptide (BNP), and renal function were evaluated. LV mass index, peak early diastolic mitral filling velocity (E), peak early diastolic mitral annular velocity (E'), and E/E' were recorded.
The E' values were significantly decreased and E/E', BNP, and hs-cTnT increased with increasing CKD stage. The CKD patients with LVDD with E' <5 cm/s had a significantly higher hs-cTnT level as well as a significantly higher BNP level compared to those with E' ≥5 cm/s. The area under the receiver-operating characteristic curve for hs-cTnT and BNP to detect E' <5 cm/s was 0.880 (p = 0.0101) and 0.741 (p = 0.0570), respectively. In multivariate analysis, hs-cTnT and albuminuria were significantly associated with E', and estimated glomerular filtration rate with the hs-cTnT level, after adjusting for age, cause of CKD, and other parameters.
These data suggest that hs-cTnT may be a useful biomarker of LVDD in non- diabetic CKD patients.
Nephron extra. 01/2011; 1(1):166-77.
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Tatsuyuki Inoue,
Hitoshi Sugiyama,
Yoshiyuki Hiki,
Keiichi Takiue, Hiroshi Morinaga,
Masashi Kitagawa,
Yohei Maeshima,
Kunihiro Fukushima,
Kazunori Nishizaki,
Hirofumi Akagi,
Yoshiki Narimatsu,
Hisashi Narimatsu,
Hirofumi Makino
[show abstract]
[hide abstract]
ABSTRACT: Aberrant O-glycosylation of serum and tonsillar IgA1 is one of the main pathogeneses of IgA nephropathy (IgAN). However, the synthesis of underglycosylated IgA1 in tonsils has not yet been characterized. This study examined tonsillar B lymphocytes of IgAN (n=34) using tonsils derived from patients with chronic tonsillitis (n=24) and sleep apnea syndrome (n=14) as a control. Gene expression of beta1,3-galactosyltransferase (beta3GalT), and the core 1 beta3GalT-specific molecular chaperone, Cosmc, UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl-transferase 2, were significantly decreased in tonsillar CD19-positive B lymphocytes from IgAN patients compared to control tonsillar tissues as determined by real-time RT-PCR. Tonsillar B cell beta3GalT gene expression significantly correlated with estimated GFR and negatively correlated with proteinuria and histological injury score. Western blotting showed the protein expression of beta3GalT in the tonsils to significantly decrease in IgAN in comparison to the controls. These data suggest the downregulation of beta3GalT in tonsillar B lymphocytes to be closely associated with the clinical characteristics of IgAN.
Clinical Immunology 09/2010; 136(3):447-55. · 4.05 Impact Factor
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Yoko Kikumoto,
Yasufumi Kai, Hiroshi Morinaga,
Mutsunori Iga-Murahashi,
Mikitaro Matsuyama,
Takashi Sasaki,
Hiroki Maruyama,
Masaaki Shimotori,
Hirofumi Makino,
Hitoshi Sugiyama,
Akihiko Okayama
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ABSTRACT: We describe two cases of Fabry disease in non-blood-related Japanese men, manifesting recurrent stroke even after the start of enzyme replacement therapy. Both exhibited chronic inflammation and ocular involvement with elevated levels of serum C reactive protein prior to the onset of stroke. We, therefore, suggest the association among persistent inflammation, ocular involvement and recurrent stroke in a certain subset of Fabry disease patients. Both cases received enzyme replacement therapy with no improvement in inflammatory signs or laboratory data. These cases suggest that Fabry disease should be considered in young patients with cryptogenic stroke or CNS manifestations and fever of unknown origin.
Internal Medicine 01/2010; 49(20):2247-52. · 0.94 Impact Factor
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ABSTRACT: We report a case of immunotactoid glomerulopathy (ITG) with cerebral hemorrhage and hypocomplementemia, with successful therapeutic outcome following the corticosteroids and antihypertensive treatment. A 70-year-old man presented with facial edema in October 2006. One day prior to his referral, he experienced speech disturbance, headache, and vomiting, and on the next day he was referred to our hospital. The laboratory examination revealed massive proteinuria (11.3 g/day) and hematuria. The total serum hemolytic complement (CH50) was decreased to 23 U/ml and C4 component was decreased to 7.5 mg/dl, whereas C3 component remained within normal limits (82 mg/dl). Brain computed tomography scan showed high-density lesions in the left parieto-occipital area suggesting subcortical cerebral hemorrhage. Renal biopsy revealed diffuse subendothelial PAS-positive depositions. Immunofluorescence studies revealed intensive deposition of IgG, IgA, C3, C1q, Fibrinogen, and kappa light chain with granular pattern in the capillary and mesangial area. Electron microscopic examination revealed regularly arranged microtubular deposits, appearing as 21-33 nm in diameter. Based on these findings, this patient was diagnosed as ITG complicated with cerebral hemorrhage and hypocomplementemia. He received oral prednisolone (30 mg/day), resulting in reduction of proteinuria, improvement of hypocomplementemia, and prevention of renal functional deterioration. This case demonstrates that accurate diagnosis of ITG may result in successful therapeutic outcome.
Clinical and Experimental Nephrology 05/2009; 13(4):378-84. · 1.37 Impact Factor
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Hitoshi Sugiyama,
Mie Maruyama, Hiroshi Morinaga,
Tatsuyuki Inoue,
Kei-Ichi Takiue,
Yoko Kikumoto,
Masaru Kinomura,
Ken-Ei Sada,
Shigeru Akagi,
Shinji Kitamura,
Yohei Maeshima,
Hirofumi Makino
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ABSTRACT: Unique renal histopathological appearances, consisting of podocytic infolding and microstructures in the glomerular basement membrane (GBM) were identified in the renal biopsies from three patients with collagen diseases such as systemic lupus erythematosus (lupus nephritis, class II) and Sjögren's syndrome. In each case, the GBM contained microstructures, including microspheres and microtubular structures, accompanied by podocytic infolding into the GBM when examined by electron microscope. The size of the microstructures in the GBM ranged from 40 to 160 nm. Glomerular endothelial cells also seemed to be infolded in the GBM in a case with lupus nephritis. The response to glucocorticoid therapy was favorable in two cases. The cause of these morphological changes in the GBM might be associated with autoimmune disorders.
Clinical and Experimental Nephrology 11/2008; 12(6):450-4. · 1.37 Impact Factor
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Naomi Fukuoka,
Hitoshi Sugiyama,
Tatsuyuki Inoue,
Yoko Kikumoto,
Kei-ichi Takiue, Hiroshi Morinaga,
Kazushi Nakao,
Yohei Maeshima,
Masato Asanuma,
Da-Hong Wang,
Keiki Ogino,
Noriyoshi Masuoka,
Hirofumi Makino
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ABSTRACT: Peritoneal fibrosis is a major complication leading to the loss of peritoneal function in patients undergoing peritoneal dialysis. However, the effect of catalase depletion on peritoneal fibrosis has not yet been investigated.
The impact of catalase deficiency on progressive peritoneal fibrosis has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 14 days.
The CG injections resulted in a thicker peritoneal membrane, reflecting peritoneal fibrosis with accumulation of interstitial type I collagen, peritoneal deposition of lipid peroxidation products (4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal), and an elevated level of 8-hydroxy-2'-deoxyguanosine in peritoneal fluid in both mouse groups on day 14. The extent of these changes, however, was significantly higher in acatalasemic mice than in wild-type mice. The level of catalase activity remained low in the acatalasemic peritoneum without the compensatory upregulation of glutathione peroxidase, but with an insufficient upregulation of superoxide dismutase activity in CG-injected mice.
Acatalasemia, therefore, exacerbates oxidant tissue injury and induces the peritoneum to develop irreversible fibrosis which is the most important complication of peritoneal dialysis. This study suggests that catalase plays a crucial role in the defense against oxidant-mediated peritoneal injury in a mouse peritoneal fibrosis model.
American Journal of Nephrology 02/2008; 28(4):661-8. · 2.54 Impact Factor
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Yoko Kikumoto,
Hitoshi Sugiyama,
Tatsuyuki Inoue, Hiroshi Morinaga,
Keiichi Takiue,
Masashi Kitagawa,
Naomi Fukuoka,
Mizuho Saeki,
Yohei Maeshima,
Da-Hong Wang,
Keiki Ogino,
Noriyoshi Masuoka,
Hirofumi Makino
[show abstract]
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ABSTRACT: Human acatalasemia may be a risk factor for the development of diabetes mellitus. However, the mechanism by which diabetes is induced is still poorly understood. The impact of catalase deficiency on the onset of diabetes has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of diabetogenic alloxan. The incidence of diabetes was higher in acatalasemic mice treated with a high dose (180 mg/kg body weight) of alloxan. A higher dose of alloxan accelerated severe atrophy of pancreatic islets and induced pancreatic β cell apoptosis in acatalasemic mice in comparison to wild-type mice. Catalase activity remained low in the acatalasemic pancreas without the significant compensatory up-regulation of glutathione peroxidase or superoxide dismutase. Furthermore, daily intraperitoneal injection of angiotensin II type 1 (AT1) receptor antagonist telmisartan (0.1 mg/kg body weight) prevented the development of alloxan-induced hyperglycemia in acatalasemic mice. This study suggests that catalase plays a crucial role in the defense against oxidative-stress-mediated pancreatic β cell death in an alloxan-induced diabetes mouse model. Treatment with telmisartan may prevent the onset of alloxan-induced diabetes even under acatalasemic conditions.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
