研究者詳細 - 和田　淳

論文 - 和田　淳

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Pathogenesis of IgA nephropathy 査読

J Wada, H Sugiyama, H Makino

SEMINARS IN NEPHROLOGY 23 ( 6 ) 556 - 563 2003年11月

Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes 査読

S Okada, K Shikata, M Matsuda, D Ogawa, H Usui, Y Kido, R Nagase, J Wada, Y Shikata, H Makino

DIABETES 52 ( 10 ) 2586 - 2593 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER DIABETES ASSOC

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression. of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.

DOI： 10.2337/diabetes.52.10.2586

Pelvic lymphocyst infection associated with maternally inherited diabetes mellitus 査読

D Ogawa, K Shikata, M Matsuda, J Wada, H Uchida, M Asada, H Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 61 ( 2 ) 137 - 141 2003年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

A 45-year-old woman with 20-year history of diabetes mellitus was admitted to our hospital because of high fever and abdominal pain. Radical hysterectomy and bilateral pelvic lymphadenectomy had been performed 4 months before admission for invasive cervical cancer. On admission, elastic hard tumors were palpable in the lower abdomen. Laboratory examination showed positive C-reactive protein (CRP), anemia and renal dysfunction. Computed tomography (CT) revealed several lymphocysts in the pelvis. She was diagnosed with infection of pelvic lymphocysts. Since her mother also had diabetes associated with deafness, we examined mitochondrial DNA in leukocytes and detected an A to G transition at the nucleotide position of 3243 (A3243G mutation). She was diagnosed as maternally inherited diabetes mellitus and deafness (MIDD). Puncture of the cysts followed by administration of antibiotics resulted in marked improvement of symptoms and laboratory findings. This is a rare case of pelvic lymphocyst infection in a patient with a mitochondrial disorder. Although the exact mechanism of infection is not clear, MIDD may represent an unusual risk factor for infection, and further investigation is necessary to assess the influence of mitochondrial dysfunction on the immune system. Pelvic lymphocyst infection should be considered in the differential diagnosis of abdominal pain and fever in patients with MIDD after abdominal surgery. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/S0168-8227(03)00120-7

Gene regulation of aldose-, aldehyde- and a renal specific oxido reductase (RSOR) in the pathobiology of diabetes mellitus 査読

FR Danesh, J Wada, EI Wallner, A Sahai, SK Srivastava, YS Kanwar

CURRENT MEDICINAL CHEMISTRY 10 ( 15 ) 1399 - 1406 2003年8月

記述言語：英語出版者・発行元：BENTHAM SCIENCE PUBL LTD

Aldose-, aldehyde and renal specific oxido reductase (RSOR) belong to the family of aldo-keto reductases (AKRs). They are monomeric (alpha/beta)8-barrel proteins with a molecular weight ranging from 30 to 40 kDa, and at present include more than 60 members. Except for RSOR, they are expressed in a wide variety of animal and plant species and in various tissues. They catalyze NADPH-dependent reduction of various aliphatic and aromatic aldehyde and ketones. During the past three decades aldehyde reductase (AKR1A) and aldose reductase (AKR1B) have been extensively investigated, and the gene regulation of AKR1B has been noted to be heavily influenced by hyperglycemic state and high glucose ambience in various culture systems. AKR1B catalyzes the conversion of glucose to sorbitol in concert with a coenzyme, NADPH. The newly discovered RSOR has certain structural and functional similarities to AKR1B and seems to be relevant to the renal complications of diabetes mellitus. Like other AKRs, it has a NADPH binding motif, however, it is located at the N-terminus and it probably undergoes Winked glycosylation in order to achieve functional substrate specificity. Besides the AKR3 motif, it has very little nucleotide or protein sequence homology with other members of the AKR family. Nevertheless, gene regulation of RSOR, like AKR1B, is heavily modulated by carbonyl, oxidative and osmotic stresses, and thus it is anticipated that its discovery would lead to the development of new inhibitors as well as gene therapy targets to alleviate the complications of diabetes mellitus in the future.

Remission and regression of diabetic nephropathy 査読

H Makino, Y Nakamura, J Wada

HYPERTENSION RESEARCH 26 ( 7 ) 515 - 519 2003年7月

記述言語：英語出版者・発行元：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

Diabetic nephropathy has become the single largest cause of end-stage renal disease (ESRD) worldwide. Until recently, it was thought that once a patient developed overt proteinuria, diabetic nephropathy was irreversible and inevitably progressed to ESRD. However, the reversal of lesions caused by diabetic nephropathy (e.g., glomerular basement membrane thickening and mesangial matrix increase) has been demonstrated in a series of patients who underwent a pancreas transplantation 10 years prior to the reversal. Remission of nephrotic range proteinuria has also been reported in some patients with type 1 diabetes from the Collaborative Study Group during a median follow-up of 3 years of angiotensin-converting enzyme (ACE) inhibitor administration; no deterioration of renal function was observed in these patients. Remission and regression in nephropathy of type 1 diabetes patients have also been reported when blood pressure was controlled aggressively. Recent clinical trials have demonstrated that angiotensin II receptor blocker (ARB) preserved renal function and slowed the progression of nephropathy to ESRD in patients with type 2 diabetes. Since many patients with type 2 diabetes manifest with a metabolic syndrome, multifactorial intensive treatment is necessary; such treatment includes behavior modifications, dietary intervention, exercise, and smoking cessation. In this population, pharmacological therapy targeting hyperglycemia, hypertension (including ARB/ACE inhibitor), and hyperlipidemia in cases of type 2 diabetes is also necessary.

DOI： 10.1291/hypres.26.515

Glomerular cell apoptosis in human lupus nephritis 査読

H Makino, H Sugiyama, Y Yamasaki, Y Maeshima, J Wada, N Kashihara

VIRCHOWS ARCHIV 443 ( 1 ) 67 - 77 2003年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER-VERLAG

Disturbed apoptosis is proposed to be involved in the pathogenesis of systemic lupus erythematosus. However, the role of renal cell apoptosis in the pathogenesis and progression of human lupus nephritis is still controversial. We have investigated glomerular cell apoptosis and the clinicopathological relationship between apoptosis and immunoserological or histological findings in 22 patients with lupus nephritis using electron microscopy and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. Resident glomerular cells as well as infiltrating neutrophils undergoing apoptosis were observed in 12 of 20 patients with lupus nephritis using electron microscopy. TUNEL-positive cells were recognized in 93% of patients with diffuse proliferative lupus nephritis (class IV) in contrast to the 20% of patients with class V. The number of TUNEL-positive cells in glomeruli significantly correlated with the level of immunoserological activity of lupus, such as anti-double-stranded DNA autoantibody and consumption of plasma complement. There was a positive correlation between glomerular cell apoptosis and the degree of proliferation in lupus nephritis. These data suggest that apoptosis is increased, but not decreased in glomeruli from patients with lupus nephritis. The signals that could induce glomerular cell apoptosis in lupus nephritis will need to be identified.

DOI： 10.1007/s00428-003-0827-x

Successful treatment of necrotizing fasciitis associated with diabetic nephropathy 査読

D Ogawa, K Shikata, J Wada, M Matsuda, H Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 60 ( 3 ) 213 - 216 2003年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

A 50-year-old woman with a 15-year history of type 2 diabetes mellitus was admitted to our hospital due to high fever and a skin lesion with severe pain, swelling and a sensation of heat in the right thigh. Laboratory examination showed elevated C-reactive protein (CRP), thrombocytopenia, nephrotic syndrome and renal dysfunction. Her blood glucose level had been well controlled. Streptococcus agalactiae was detected in both the skin lesion and blood culture, and pathological examination revealed neutrophil infiltration in the fascia and muscle layer. The patient was diagnosed with necrotizing fasciitis, septic shock and disseminated intravascular coagulation. A combination therapy of antibiotics and suraical debridement resulted in the improvement of symptoms as supported by laboratory findings, and the skin lesion also showed improvement. Although group A streptococcus is well known to be implicated in the pathogenesis of necrotizing fasciitis, only S. agalacticie, belonging to group B streptococcus, was isolated from the tissue and blood cultures in this case. Although this organism is not virulent and rarely causes a necrotizing fasciitis, both the superficial fascial layer and underlying muscle were affected in this case. There have been only a few reports of necrotizing fasciitis due to S. agalactiae in patients with diabetes mellitus. Although the blood glucose level was well controlled in our patient, this disease might be caused by other factors, including diminished sense of touch and pain, abnormality of microcirculation and hypogammaglobulinemia due to nephrotic syndrome. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0168-8227(03)00034-2

Imprinted mesodermal specific transcript (MEST) and H19 genes in renal development and diabetes 査読

YS Kanwar, XM Pan, S Lin, A Kumar, J Wada, CS Haas, G Liau, JW Lomasney

KIDNEY INTERNATIONAL 63 ( 5 ) 1658 - 1670 2003年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL PUBLISHING INC

Background. Imprinted genes, mesodermal specific cDNA or transcript (MEST) and H19, are implicated in peri-implantation embryogenesis, and their expression was assessed in embryonic kidneys undergoing glucose-induced dysmorphogenesis.
Methods. MEST and H19 mRNA expression was assessed by Northern blot analysis in embryonic kidneys of mice harvested at day 15 to day 19 of gestation and of 1-week-old mice obtained from hyperglycemic mothers. A full-length mouse MEST cDNA was isolated, subcloned into an expression vector, a recombinant protein prepared and an antibody raised; the latter was used to assess protein expression by immunoprecipitation and immunofluorescence microscopy in day 13 metanephric explants subjected to high glucose ambience. Also, MEST mRNA expression was assessed in high d glucose-treated explants by competitive reverse transcription-polymerase chain reaction (RT-PCR) analyses and by in situ tissue autoradiography.
Results. A high expression of MEST and H19 with respective transcript size of similar to2.7 and similar to2.4 kb was observed in fetal kidneys, and their expression decreased during the successive stages of gestation and was undetectable in the postnatal period. At day 13, the MEST mRNA was expressed in the mesenchyme, while H19 was expressed in the ureteric bud branches and epithelial elements of the metanephros. Their expression decreased with progression of gestation. By competitive RT-PCR and Northern blot and in situ autoradiographic analyses, both MEST and H19 expressions decreased in day 13 explants treated with high glucose and in the kidneys of fetuses obtained from diabetic mothers. The MEST protein expression was observed in the metanephric epithelial elements and ureteric bud branches instead of in the mesenchyme, and its expression decreased in glucose-treated dysmorphogenetic explants, as assessed by immunofluorescence and immunoprecipitation methods.
Conclusion. MEST and H19 imprinted genes are strategically located in the mammalian embryonic metanephros. They are developmentally regulated and their concomitant decreased expression in high glucose ambience or diabetic state did not follow the prevailing dogma of reciprocal inactivation/activation of imprinted genes, and such a decrease may be responsible for the perturbed epithelial:mesenchymal interactions leading to dysmorphogenesis of the mammalian metanephros.

DOI： 10.1046/j.1523-1755.2003.00905.x

Perturbation of autocrine/paracrine loops of burst-forming units of erythroid-derived cells in rHuEPO-hyporesponsive hemodialysis patients 査読

K Nakao, J Wada, K Ota, H Ichikawa, S Akagi, A Okamoto, K Hida, Y Nagake, H Makino

AMERICAN JOURNAL OF KIDNEY DISEASES 41 ( 3 ) 624 - 636 2003年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO

Background: Quantitative or qualitative abnormalities of erythroid progenitors in patients with chronic renal failure (CRF) could be the major factor for recombinant human erythropoietin (rHuEPO) hyporesponsiveness and severe anemia in hemodialysis (HD) patients receiving rHuEPO therapy. Methods Purified 1 x 10(4) circulating CD34(+) cells isolated from rHuEPO-hyporesponsive HD patients (EPO-H; n = 10), rHuEPO-responsive non-HD patients with CRF (EPO-R; n = 8), nonanemic HD patients without rHuEPO therapy (EPO-W/O; n = 10), and healthy volunteer controls (CON; n = 10) were subjected to a methylcellulose culture system supplemented with rHuEPO, recombinant human interleukin-3 (IL-3), recombinant human stem cell factor (SCF), and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) for 14 days. Results: The average number of burst-forming units of erythroids (BFU-Es) was significantly less in the EPO-H group compared with the CON and EPO-W/O groups. Furthermore, colony size also was significantly smaller in the EPO-H group. Total RNAs were extracted from approximately 100 colonies/patient and subjected to complementary DNA expression array studies of 268 growth factors, cytokines, chemokines, and their receptors. A characteristic cluster upregulated in the EPO-R and EPO-W/O groups and downregulated in the EPO-H group was identified that contained various cytokines and growth factors, including IL-6, GM-CSF, vascular endothelial growth factor 13, IL-9, IL-3, leukemia inhibitory factor, and interferon alpha-2, and such receptors as thrombopoietin receptor, IL-9 receptor, and colony-stimulating factor 1 receptor. Conclusion: These data suggest that the cross-talk network or autocrine/paracrine regulatory loop is critically impaired in BFU-E-derived cells in EPO-H patients, and investigation of these cluster genes would facilitate the development of novel therapeutic strategies for such patients.

DOI： 10.1053/ajkd.2003.50124

HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats 査読

H Usui, K Shikata, M Matsuda, S Okada, D Ogawa, T Yamashita, K Hida, M Satoh, J Wada, H Makino

NEPHROLOGY DIALYSIS TRANSPLANTATION 18 ( 2 ) 265 - 272 2003年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Background. An inflammatory process may be one of the critical factors that contribute to the development of diabetic nephropathy (DN). We reported previously that intercellular adhesion molecule-1 (ICAM-1) is up-regulated and promotes macrophage infiltration in the glomeruli of diabetic rats. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have recently been emphasized to have anti-inflammatory effects; inhibition of leukocyte adhesion and migration, independent of the cholesterol-lowering effect. The present study was designed to test the hypothesis that statins prevent the development of DN by pleiotropic effects.
Methods. Streptozotocin-induced diabetic rats were treated with cerivastatin (0.5 mg/kg body weight) or vehicle for 4 weeks. We analysed glomerular macrophage infiltration and ICAM-1 expression. We also evaluated major regulators of ICAM-1, activation of nuclear factor-kappa B (NF-kappaB) using electrophoretic mobility shift assay, and oxidative stress.
Results. Statin treatment reduced urinary albumin excretion (UAE) (2.96 +/- 0.18 vs 2.38 +/- 0.06; log 10 UAE, P<0.05), glomerular size (12 150 329 vs 9963+/-307 mum(2), P<0.05), and lowered blood pressure, compared with untreated diabetic rats. Immunohistochemistry revealed that macrophage infiltration and ICAM-1 expression in glomeruli were increased in diabetic rats and were inhibited by statin treatment. Renal NF-kappaB activity, urinary excretion and renal deposition of 8-OHdG were increased in diabetic rats, and reduced by statin treatment.
Conclusion. Statin treatment prevented glomerular injury, independent of the cholesterol-lowering effects. Our findings suggest that the beneficial effect might be mediated by pleiotropic effects including an anti-inflammatory action through a reduction of oxidative stress, NF-kappaB activation, ICAM-1 expression and macrophage infiltration in the early phase of DN.

DOI： 10.1093/ndt/18.2.265

Erratum: HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats (Nephrology Dialysis Transplantation (2003) vol. 18 (265-272))

Usui, H., Shikata, K., Matsuda, M., Okada, S., Ogawa, D., Yamashita, T., Hida, K., Satoh, M., Wada, J., Makino, H.

Nephrology Dialysis Transplantation 18 ( 7 ) 1418 - 1418 2003年

Protective effect of a novel and selective inhibitor of inducible nitric oxide synthase on experimental crescentic glomerulonephritis in WKY rats 査読

D Ogawa, K Shikata, M Matsuda, S Okada, H Usui, J Wada, N Taniguchi, H Makino

NEPHROLOGY DIALYSIS TRANSPLANTATION 17 ( 12 ) 2117 - 2121 2002年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Background. Nitric oxide (NO) plays important roles in a variety of pathophysiological processes. It has been reported that inducible NO synthase (iNOS) is upregulated in the glomeruli of patients with glomerulonephritis, although there has been no direct evidence that NO generated by iNOS contributes to the progression of glomerulonephritis. ONO-1714, a novel cyclic amidine analog, is a selective inhibitor of iNOS. To elucidate the role of iNOS in the pathogenesis of experimental crescentic glomerulonephritis, we examined the effect of ONO-1714 given to rats with nephrotoxic serum (NTS) nephritis.
Methods. We induced NTS nephritis in Wistar-Kyoto (WKY) rats. These rats were given ONO-1714 or physiological saline intraperitoneally for 14 days using an osmotic pump after intraperitoneal injection with NTS.
Results. Glomerular expression of iNOS and urinary excretion of NO metabolites (nitrite/nitrate) were increased in rats after injection of NTS. As compared with the control group, ONO-1714 significantly reduced proteinuria, crescent formation, glomerular infiltration of macrophages and urinary excretion of nitrite/nitrate.
Conclusion. The present results suggest that NO radicals generated by iNOS contribute to the progression of experimental crescentic glomerulonephritis in WKY rats. The selective iNOS inhibitor ONO-1714 may be beneficial for the treatment of crescentic glomerulonephritis.

Daily walking reduces visceral adipose tissue areas and improves insulin resistance in Japanese obese subjects 査読

N Miyatake, H Nishikawa, A Morishita, M Kunitomi, J Wada, H Suzuki, K Takahashi, H Makino, S Kira, M Fujii

DIABETES RESEARCH AND CLINICAL PRACTICE 58 ( 2 ) 101 - 107 2002年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

Objective: It is known that the accumulation of abdominal fat is one of the risk factors for atherosclerosis. Although exercise is commonly prescribed to reduce body weight, the efficacy of low intensity exercise for the reduction of abdominal visceral adipose tissue remains to be investigated. Research design and methods: Thirty one obese Japanese males (body mass index (BMI) greater than or equal to 25) ranging in age from 32 to 59, participated in a 1-year follow up study and they were instructed to have a modest increase in daily activity and record their daily walking. Before and after exercise prescription, body composition, blood pressure, physical fitness i.e. aerobic exercise level, muscle strength and flexibility were recorded. Insulin resistance was evaluated using a homeostasis model assessment, the HOMA index. Results: HOMA index, parameters of body composition, blood pressure, triglyceride and HDL cholesterol were significantly improved. The aerobic exercise level, leg strength, weight-bearing index (leg strength/body weight) and the steps taken per day were significantly increased. By stepwise multiple regression analysis, Deltavisceral adipose tissue area was the major determinant for DeltaHOMA index. (DeltaHOMA index = -0.386+0.016 Deltavisceral adipose tissue area, r(2) = 0.267, P < 0.01). Exercise capacity and calorie intake were not significantly related to Deltavisceral adipose tissue area, while Deltasteps per day was significantly correlated with Deltavisceral adipose tissue area (Deltavisceral adipose tissue area = -21.363-0.004Delta steps per day, r(2) = 0.184, P = 0.0326). Conclusions: Taken together, intra-abdominal visceral adipose tissue is critically involved in insulin resistance and daily walking rather than improvement of exercise capacity correlated with the reduction of visceral adipose tissue in obese Japanese males. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0168-8227(02)00129-8

Therapeutic effect of sulphated hyaluronic acid, a potential selectin-blocking agent, on experimental progressive mesangial proliferative glomerulonephritis 査読

M Matsuda, K Shikata, F Shimizu, Y Suzuki, M Miyasaka, H Kawachi, H Kawashima, J Wada, H Sugimoto, Y Shikata, D Ogawa, SJ Tojo, K Akima, H Makino

JOURNAL OF PATHOLOGY 198 ( 3 ) 407 - 414 2002年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS LTD

The initial event in the process of leukocyte infiltration is characterized by leukocyte rolling on the surface of the endothelium, which is mediated by selectins. P- and L-selectin bind to the sulphated sugar chains of their natural ligands, including sulphated glycolipids such as sulphatide. Recently, it has been demonstrated that sulphated glycolipids and sulphated oligosaccharides interfere with selectin binding pathways. This study synthesized sulphated hyaluronic acid (SHA), which is a potential selectin-blocking agent, and examined its therapeutic effect on the experimental progressive mesangial proliferative glomerulonephritis induced by anti-Thy-1 monoclonal antibody (1-22-3 MAb) after unilateral nephrectomy. The selectin-inhibitory effect of SHA in vitro was confirmed. SHA inhibited the binding of P- and L-selectin to sulphatide, which is a glycolipid ligand for P- and L-selectin, at a concentration of 1.5 mug/ml and 100 mug/ml. Immunohistochemical examination showed that P-selectin was up-regulated in the glomeruli in the 1-22-3 MAb nephritis model, while the ligands for L-selectin were not detected in the glomerular tufts. A single administration of SHA ameliorated proteinuria and glomerular leukocyte infiltration in 24 h after the injection of anti-Thy-1 MAb. Anti-P-selectin MAb, but not anti-L-selectin MAb, inhibited proteinuria and glomerular leukocyte infiltration. To examine further the therapeutic effect of SHA on chronic glomerulonephritis, SHA was administered daily from day 3 to day 14 in this model. Proteinuria and glomerular leukocyte infiltration were significantly diminished in SHA-treated rats on day 14. These results suggest that SHA ameliorated rat progressive mesangial proliferative glomerulonephritis by inhibiting P-selectin-dependent leukocyte infiltration in glomeruli. Sulphated oligosaccharides may be beneficial for the therapy of mesangial proliferative glomerulonephritis. Copyright (C) 2002 John Wiley Sons, Ltd.

DOI： 10.1002/path.1209

Beraprost sodium, prostacyclin analogue, attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats 査読

T Yamashita, K Shikata, M Matsuda, S Okada, D Ogawa, H Sugimoto, J Wada, H Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 57 ( 3 ) 149 - 161 2002年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

Stable prostacyclin analogue, beraprost sodium (BPS) has recently been reported to attenuate glomerular hyperfiltration in diabetic rats, however, the mechanism has been still unknown. We previously reported that overexpression of endothelial cell nitric oxide synthase (ecNOS) in afferent arterioles and glomeruli induce inappropriate dilatation of afferent arterioles and glomerular hyperfiltration through overproduction of nitric oxide in early stage of diabetic nephropathy. In this study, we tested the hypothesis that BPS ameliorates glomerular hyperfiltration through modulating ecNOS expression in diabetic nephropathy. Furthermore, we examined the effects of BPS on the expression of intercellular adhesion molecule-1 (ICAM-1) and macrophage infiltration in diabetic glomeruli, because glomerular hyperfiltration induces the expression of ICAM-1 resulting in macrophage infiltration. Male Sprague Dawley (SD) rats were administered continuously with BPS for 4 weeks after induction of diabetes by streptozotocin. In diabetic rats, the diameters of afferent arterioles, glomerular volume, creatinine clearance and urinary excretion of albumin and NO2/NO3 were increased as compared with non-diabetic control rats. Treatment with BPS improved these changes. The expression of ecNOS was increased in afferent arterioles and glomeruli in diabetic rats and suppressed by BPS. Prostacyclin receptor was expressed along afferent arterioles. Our results suggest that BPS attenuates glomerular hyperfiltration by modulating ecNOS expression in early stage of diabetic nephropathy. Moreover, BPS may inhibit ICAM-1-dependent infiltration of macrophages in diabetic glomeruli. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0168-8227(02)00054-2

A case of congenital generalized lipodystrophy with lipoatrophic diabetes developing anti-insulin antibodies 査読

H Usui, K Shikata, J Wada, T Sugimoto, J Yamana, T Oishi, M Matsuda, M Yoneda, Koshima, I, H Makino

DIABETIC MEDICINE 19 ( 9 ) 794 - 795 2002年9月

Isolation and functional analysis of mouse UbA52 gene and its relevance to diabetic nephropathy 査読

L Sun, XM Pan, J Wada, CS Haas, RP Wuthrich, FR Danesh, SS Chugh, YS Kanwar

JOURNAL OF BIOLOGICAL CHEMISTRY 277 ( 33 ) 29953 - 29962 2002年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

In delineating the mechanism(s) of diabetic nephropathy various novel genes have been isolated, whereas others remain to be discovered. We identified several up-regulated genes in the kidneys of diabetic newborn mice. Among them was UbA52, a ubiquitin ribosomal fusion protein. Its mRNA expression in the kidney was proportional to blood glucose levels. By in situ hybridization and immunohistochemistry, UbA52 was exclusively localized to renal tubules, and its expression was markedly increased in diabetic mice. The up-regulated UbA52 mRNA and protein expression were also observed in Madin-Darby canine kidney cells, a tubular cell line, treated with 30 mm glucose in both cell lysates and ribosomal fractions. To explore the mechanism(s) of its increased expression, UbA52 genomic DNA was isolated. A transcription start site at -22 by from the initiation codon was identified and confirmed by primer extension analysis. The UbA52 promoter region included glucose response-related E-box sequences and stress response elements (STRE). Unlike in humans, mouse UbA52 gene had no introns in the coding or 5'-ATG-flanking regions. To identify the DNA segment with maximal promoter activity, deletion constructs were prepared using a pSEAP vector system and transfected into COS7 kidney cells. Maximal activity was confined to -198 to +68 bp, which included E-boxes and STRE motifs. A dose-dependent increase in the promoter activity was observed in cells exposed to high glucose. Mutations in the first E-box (CAGCTG --> TGGCTG) or STRE (CCCCT --> CATCT) resulted in a decrease in the SEAP activity under high glucose ambience. Given the presence of glucose-responsive motifs in the promoter region and decrease in the SEAP activity in E-box mutants in the presence of glucose, these data suggest that UbA52, a ribosomal fusion protein, may be relevant in the pathogenesis of diabetic nephropathy.

DOI： 10.1074/jbc.M204665200

Preventive effect of sulphated colominic acid on P-selectin-dependent infiltration of macrophages in experimentally induced crescentic glomerulonephritis 査読

D Ogawa, K Shikata, M Matsuda, S Okada, J Wada, S Yamaguchi, Y Suzuki, M Miyasaka, S Tojo, H Makino

CLINICAL AND EXPERIMENTAL IMMUNOLOGY 129 ( 1 ) 43 - 53 2002年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL PUBLISHING LTD

Leucocytes infiltrate into renal tissue and are involved in the pathogenesis of crescentic glomerulonephritis. The initial event in the process of leucocyte infiltration is characterized by selectin-mediated leucocyte rolling on endothelial surface. Role of selectins in pathogenesis of glomerulonephritis has still been controversial. Sulphated glycolipids and sulphated polysaccharides interfere with the binding of P- and L-selectin with carbohydrate ligands on endothelial cells or on leucocytes. Here we evaluated the role of selectins and the preventive effects of sulphated colominic acid (SCA), a synthetic sulphated polysaccharide, on experimental crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats. Crescentic glomerulonephritis was induced by injection of nephrotoxic serum (NTS) in WKY rats. Rats subsequently received intraperitoneal injection of saline, neutralizing or non-neutralizing monoclonal antibody (mAb) to rat P-selectin and L-selectin, SCA (5 or 10mg/kg/day) or nonsulphated colominic acid (CA) (10mg/kg/day) for 2 weeks. Localization of P-, E-selectin, ligands for L-selectin and intraglomerular leucocytes was examined by immunohistochemistry. Gene expression of platelet-derived growth factor (PDGF) B chain in glomeruli was quantified using real-time RT-PCR. P-selectin was highly expressed on glomerular endothelial cells after injection of NTS, whereas E-selectin and L-selectin ligands were not detected. Anti-P-selectin mAb, but not anti-L-selectin mAb, significantly reduced glomerular infiltration of macrophages, crescent formation, and proteinuria. SCA also reduced proteinuria, macrophage infiltration, and crescent formation in a dose-dependent manner. Furthermore, SCA suppressed gene expression of PDGF B chain in glomeruli. Our results indicate that P-selectin partially mediate glomerular infiltration of macrophage in experimental crescentic glomerulonephritis. Moreover, SCA may inhibit intraglomerular infiltration of macrophages by interfering with P-selectin-dependent adhesion pathway, and progression of experimental crescentic glomerulonephritis.

DOI： 10.1046/j.1365-2249.2002.01875.x

Identification of developmentally regulated mesodermal-specific transcript in mouse embryonic metanephros 査読

YS Kanwar, A Kumar, K Ota, S Lin, J Wada, S Chugh, EI Wallner

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 282 ( 5 ) F953 - F965 2002年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER PHYSIOLOGICAL SOC

Mesodermal-specific cDNA or transcript (MEST) was identified by suppression subtractive hybridization-PCR of cDNA isolated from embryonic day 13 vs. newborn mice kidneys. At day 13 of mouse gestation, a high expression of MEST, with a single similar to2.7-kb transcript that was exclusively localized to the metanephric mesenchyme was observed. The MEST mRNA expression gradually decreased during the later stages and then abruptly decreased in the newborn kidneys and subsequent postnatal life, after which a very mild expression persisted in the glomerular mesangium. Regression in mRNA expression during embryonic renal development appears to be related to methylation of the MEST gene. Treatment of metanephroi, harvested at day 13 of gestation with MEST-specific antisense oligodeoxynucleotide resulted in a dose-dependent decrease in the size of the explants and the nephron population. This was associated with a selective decrease in MEST mRNA expression and accelerated apoptosis of the mesenchyme. These findings suggest that MEST, a gene with a putative mesenchymal cell-derived protein, conceivably plays a role in mammalian metanephric development.

DOI： 10.1152/ajprenal.00200.2001

Minimal change nephrotic syndrome developing during postoperative interferon-beta therapy for malignant melanoma 査読

K Nakao, H Sugiyama, E Makino, H Matsuura, A Ohmoto, T Sugimoto, H Ichikawa, J Wada, Y Yamasaki, H Makino

NEPHRON 90 ( 4 ) 498 - 500 2002年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

A 64-year-old man presented with proteinuria during postoperative interferon (IFN)-beta therapy against malignant melanoma. Renal pathologic findings were consistent with minimal change nephrotic syndrome (MCNS) showing extensive foot process effacement of visceral glomerular epithelial cells (podocyte). Nephrotic range proteinuria gradually regressed after stoppage of local injection of IFN-beta without glucocorticoid treatment. To our knowledge this is the first report that demonstrates histological abnormalities of the glomerulus associated with postoperative IFN-beta therapy for the malignant melanoma. Copyright (C) 2002 S. Karger AG, Basel.

DOI： 10.1159/000054740

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