研究者詳細 - 和田　淳

論文 - 和田　淳

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Procollagen C-proteinase enhancer-1 (POPE-1) interacts with beta 2-microglobulin (beta 2-m) and may help initiate beta 2-m amyloid fibril formation in connective tissues 査読

Hisanori Morimoto, Jun Wada, Bernard Font, Joni D. Mott, David J. S. Hulmes, Tadakazu Ookoshi, Hironobu Naiki, Akihiro Yasuhara, Atsuko Nakatsuka, Kousuke Fukuoka, Yuji Takatori, Haruo Ichikawa, Shigeru Akagi, Kazushi Nakao, Hirofumi Makino

MATRIX BIOLOGY 27 ( 3 ) 211 - 219 2008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：ELSEVIER SCIENCE BV

Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although beta 2-microglobulin (beta 2-m) is the major structural component of beta 2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhance-1 (POPE-1) as a new interacting protein with beta 2-m by screening a human synovium cDNA library. The interaction of beta 2-m with full-length POPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, beta 2-m appeared to interact with POPE-1 via the NTR (netrin-like) domain and not via the CUB (C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, beta 2-m co-localized and formed a complex with POPE-1. beta 2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate beta 2-m amyloid fibril formation from monomeric beta 2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of beta 2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of beta 2-m may be linked to subsequent beta 2-m amyloid fibril formation, the disruption of the interaction between beta 2-m and POPE-1 may prevent beta 2-m amyloid fibril formation and therefore POPE-1 could be a new target for the treatment of DRA. (C) 2007 Elsevier B.V./International Society of Matrix Biology. All rights reserved.

DOI： 10.1016/j.matbio.2007.11.005

Vaspin: a novel serpin with insulin-sensitizing effects 査読

Jun Wada

EXPERT OPINION ON INVESTIGATIONAL DRUGS 17 ( 3 ) 327 - 333 2008年3月

記述言語：英語出版者・発行元：INFORMA HEALTHCARE

Background: A variety of substances, including free fatty acids, leptin, tumor necrosis factor-a, acylation-stimulating protein, adiponectin, and resistin, are secreted by adipocytes. They modulate insulin sensitivity and are new therapeutic targets in metabolic syndrome. Objective: To identify novel adipokines derived from visceral adipose tissues. Method: We used the PCR-based cDNA subtraction method to screen the genes predominantly expressed in visceral white adipose tissues (WATs) in Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of abdominal obesity and type 2 diabetes. Results/conclusions: We identified the vaspin gene (Serpina12) which is upregulated in visceral WATs of OLETF rats. Vaspin mRNA was barely detectable at 6 weeks of age and it was abundantly and exclusively expressed in visceral WATs at 30 weeks of age, when OLETF rats reach their peak body weight. However, vaspin mRNA decreased with worsening of diabetes and body weight loss. Vaspin mRNA increased with treatment of thiazolidinediones (pioglitazone). Administration of recombinant vaspin into high-fat high-sucrose chow-induced obese ICR mice improved glucose tolerance and insulin sensitivity. Vaspin may be the compensatory molecule in the pathogenesis of metabolic syndrome and vaspin recombinant protein or vaspin-mimicking agents such as vaspin analogs, antibodies or small molecule agents may be the link to drug discovery and development.

DOI： 10.1517/13543784.17.3.327

Diabetic nephropathy: Mechanisms of renal disease progression 査読

Yashpal S. Kanwar, Jun Wada, Lin Sun, Ping Xie, Elisabeth I. Wallner, Sheldon Chen, Sumant Chugh, Farhad R. Danesh

EXPERIMENTAL BIOLOGY AND MEDICINE 233 ( 1 ) 4 - 11 2008年1月

記述言語：英語出版者・発行元：SAGE PUBLICATIONS LTD

Diabetic nephropathy is characterized by excessive amassing of extracellular matrix (ECM) with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. In view of this outcome, it would mean that all the kidney cellular elements, i.e., glomerular endothelia, mesangial cells, podocytes, and tubular epithelia, are targets of hyperglycemic injury. Conceivably, high glucose activates various pathways via similar mechanisms in different cell types of the kidney except for minor exceptions that are related to the selective expression of a given molecule in a particular renal compartment. To begin with, there is an obligatory excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products (AGEs), activation of protein kinase C (PKC), increased expression of transforming growth factor-p (TGF-beta), GTP-binding proteins, and generation of reactive oxygen species (ROS). The ROS seem to be the common denominator in various pathways and are central to the pathogenesis of hyperglycemic injury. In addition, there are marked alterations in intraglomerular hemodynamics, i.e., hyperfiltration, and this along with metabolic derangements adversely compounds the hyperglycemia-induced injury. Here, the information compiled under various subtitles of this article is derived from an enormous amount of data summarized in several excellent literature reviews, and thus their further reading is suggested to gain in-depth knowledge of each of the subject matter.

DOI： 10.3181/0705-MR-134

Comparison of serum uric acid levels between Japanese with and without metabolic syndrome

Numata, T., Miyatake, N., Wada, J., Makino, H.

Diabetes Research and Clinical Practice 80 ( 1 ) 2008年

Vaspin and insulin resistance

Wada, J.

Rinsho byori. The Japanese journal of clinical pathology 56 ( 8 ) 2008年

Association of single-nucleotide polymorphisms in MTMR9 gene with obesity 査読

Takahiro Yanagiya, Atsushi Tanabe, Aritoshi Iida, Susumu Saito, Akihiro Sekine, Atsushi Takahashi, Tatsuhiko Tsunoda, Seika Kamohara, Yoshio Nakata, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Hiroaki Masuzaki, Masato Yoneda, Atsushi Nakajima, Shigeru Miyazaki, Katsuto Tokunaga, Manabu Kawamoto, Tohru Funahashi, Kazuyuki Hamaguchi, Kiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Kazuwa Nakao, Toshiie Sakata, Yuji Matsuzawa, Naoyuki Kamatani, Yusuke Nakamura, Kikuko Hotta

HUMAN MOLECULAR GENETICS 16 ( 24 ) 3017 - 3026 2007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

Genetic factors are clearly involved in the development of obesity, but the genetic background of obesity remains largely unclear. Starting from 62 663 gene-based single-nucleotide polymorphisms (SNPs) in three sequential case-control association studies, we identified a replicated association between the obesity phenotype (BMI >= 30 kg/m(2)) and a SNP (rs2293855) located in the myotublarin-related protein 9 (MTMR9) gene in the chromosomal segment 8p23-p22. P-values (minor allele dominant model) of the first set (93 cases versus 649 controls) and the second set (564 cases versus 562 controls) were 0.008 and 0.0002, respectively. The association was replicated in the third set [394 cases versus 958 controls, P=0.005, odds ratio (95% CI) =1.40 (1.11-1.78)]. The global P= value was 0.0000005. A multiple regression analysis revealed that gender, age BMI and rs2293855 genotype (minor allele dominant model) were significantly associated with both systolic and diastolic blood pressures. MTMR9 was shown to be the only gene within the haplotype block that contained SNPs associated with obesity. Both the transcript and protein of MTMR9 were detected in the rodent lateral hypothalamic area as well as in the arcuate nucleus, and the protein co-existed with orexin, melanin concentrating hormone, neuropeptide Y and proopiomelanocortin. The levels of MTMR9 transcript in the murine hypothalamic region increased after fasting and were decreased by a high-fat diet. Our data suggested that genetic variations in MTMR9 may confer a predisposition towards obesity and hypertension through regulation of hypothalamic neuropeptides.

DOI： 10.1093/hmg/ddm260

Collectrin, a homologue of ACE2, its transcriptional control and functional perspectives 査読

Yanling Zhang, Jun Wada

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 363 ( 1 ) 1 - 5 2007年11月

記述言語：英語出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Collectrin is a type I membrane protein and shares significant homology with C-terminal domain of angiotensin-converting enzyme-2 (ACE2). However, collectrin lacks catalytic domain and it suggests the presence of uncharacterized physiological functions of collectrin. Collectrin is transcriptionally regulated by hepatocyte nuclear factor-alpha and -beta and is highly expressed on renal proximal tubules and collecting ducts as well as pancreatic beta-cells. Recent in vitro and in vivo studies demonstrated interesting physiological roles of collectrin related to insulin secretion, formation of primary cilia, renal cyst formation and amino acid transport. The common underlying molecular mechanism may be suggested by the evidence that collectrin binds to SNARE complex by interacting with snapin. Collectrin is involved in the process of vesicle transport and membrane fusion and thus it delivers insulin for exocytosis or various membrane proteins to apical plasmalemma and primary cilia. Collectrin may be the new therapeutic target for various pathological processes such as diabetes, polycystic kidney disease, hypertension and aminoaciduria. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.08.136

Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells 査読

Kazuyoshi Omori, Yasushi Shikata, Kei Sarai, Naomi Watanabe, Jun Wada, Noriko Goda, Noriyuki Kataoka, Kenichi Shikata, Hirofumi Makino

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 293 ( 5 ) C1523 - C1531 2007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：AMER PHYSIOLOGICAL SOC

Edaravone is a potent scavenger of hydroxyl radicals and is quite successful in patients with acute cerebral ischemia, and several organ-protective effects have been reported. Treatment of human microvascular endothelial cells with edaravone (1.5 mu M) resulted in the enhancement of transmonolayer electrical resistance coincident with cortical actin enhancement and redistribution of focal adhesion proteins and adherens junction proteins to the cell periphery. Edaravone also induced small GTPase Rac activation and focal adhesion kinase (FAK; Tyr(576)) phosphorylation associated with sphingosine-1-phosphate receptor type 1 (S1P(1)) transactivation. S1P(1) protein depletion by the short interfering RNA technique completely abolished edaravone-induced FAK ( Tyr576) phosphorylation and Rac activation. This is the first report of edaravone-induced endothelial barrier enhancement coincident with focal adhesion remodeling and cytoskeletal rearrangement associated with Rac activation via S1P(1) transactivation. Considering the well-established endothelial barrier-protective effect of S1P, endothelial barrier enhancement as a consequence of S1P(1) transactivation may at least partly be the potent mechanisms for the organ-protective effect of edaravone and is suggestive of edaravone as a therapeutic agent against systemic vascular barrier disorder.

DOI： 10.1152/ajpcell.00524.2006

Linkage between oxygen uptake at ventilatory threshold and muscle strength in subjects with and without metabolic syndrome 査読

Nobuyuki Miyatake, Takeshi Saito, Jun Wada, Hidetaka Nishikawa, Sumiko Matsumoto, Motohiko Miyachi, Masafumi Fujii, Hirofumi Makino, Takeyuki Numata

ACTA MEDICA OKAYAMA 61 ( 5 ) 255 - 259 2007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：OKAYAMA UNIV MED SCHOOL

We evaluated the linkage between oxygen uptake at the ventilatory threshold (VT) and muscle strength in subjects with and without metabolic syndrome. We used data of 226 Japanese men with metabolic syndrome and 265 Japanese men without the syndrome. Metabolic syndrome has recently been defined by a new criterion in Japan. Oxygen uptake at VT and muscle strength, i.e. grip strength and leg strength were measured. Oxygen uptake at VT and muscle strength/body weight were found to be significantly lower in subjects with metabolic syndrome than in those without the syndrome. However, the differences did not reach significant levels after adjusting for leg strength/body weight or oxygen uptake at VT. A combination of aerobic exercise and resistance training might be considered for preventing and improving metabolic syndrome.

DOI： 10.18926/AMO/32895

Comparison of ventilatory threshold and exercise habits between Japanese men with and without metabolic syndrome 査読

Nobuyuki Miyatake, Takeshi Saito, Jun Wada, Motohiko Miyachi, Izumi Tabata, Sumiko Matsumoto, Hidetaka Nishikawa, Hirofumi Makino, Takeyuki Numata

DIABETES RESEARCH AND CLINICAL PRACTICE 77 ( 2 ) 314 - 319 2007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 IRELAND LTD

Objective: We compared the levels of ventilatory threshold (VT) and exercise habits in subjects with metabolic syndrome with those in age, sex-matched subjects without metabolic syndrome.
Methods: We used data of 155 Japanese men (47.1 +/- 9.2 years) with metabolic syndrome; the diagnosis was given by the definition and the diagnostic standard for metabolic syndrome in Japan. The influence of metabolic syndrome on oxygen uptake, work rate and heart rate at VT, and exercise habits were evaluated.
Results: Oxygen uptake and work rate at VT in subjects with metabolic syndrome were significantly lower than those in subjects without metabolic syndrome even after adjusting for body mass index (BMI). The number of subjects with exercise habits was significantly lower in metabolic syndrome. The subjects with exercise habits were significantly older than that in subjects without exercise habits. Furthermore, oxygen uptake and work rate at VT were significantly higher in subjects with exercise habits than those in subjects without exercise habits.
Conclusion: Lower level of VT was characteristic in subjects with metabolic syndrome. Promotion of exercise habits is necessary for preventing and improving metabolic syndrome in Japanese men. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2006.11.008

Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients 査読

Ritsuko Yoshikawa, Jun Wada, Kousuke Seiki, Takashi Matsuoka, Satoshi Miyamoto, Kenji Takahashi, Sachiko Ota, Kazuhi Taniai, Kazuyuki Hida, Minoru Yamakado, Kenichi Shikata, Yoshio Uehara, Yoshihiro Urade, Hirofumi Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 76 ( 3 ) 358 - 367 2007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 IRELAND LTD

Background: The presence of metabolic syndrome has been shown to be predictors of cardiovascular morbidity and mortality in patients with type 2 diabetes. In a cross-sectional clinical study, we investigated the association of metabolic syndrome with asymptomatic lacunar strokes and cardiovascular disease (CVD) and we compared its significance with urinary protein markers.
Methods: We studied Japanese type 2 diabetes patients (n = 233, men = 124, women = 109). The diagnosis of metabolic syndrome was made according to WHO and International Diabetes Federation (IDF) criteria. Cardiovascular events were recorded and asymptomatic lacunar lesions were evaluated with magnetic resonance imaging (MRI). We also measured urinary levels of albumin, type IV collagen, beta 2-microglobulin (beta 2MG), N-acetyl-beta-D-glucosaminidase (NAG) and lipocalin-type prostaglandin D synthase (PGDS).
Results: The prevalence of metabolic syndrome is 31.3% (IDF) and 52% (WHO) in 233 patients and microalbuminuria was present in 62 subjects (26.6%). Metabolic syndrome (WHO) significantly associated with asymptomatic lacunar lesions (p = 0.035, OR = 2.854, CI 1.075-7.579), while metabolic syndrome (IDF) or urinary markers failed to associate with presence of asymptomatic lacunar lesions. The presence of metabolic syndrome or microalbuminuria did not show significant association with CVD; however, the elevation of beta 2MG, NAG and PGDS showed significant association with CVD. By a logistic regression analysis using urinary proteins as independent variables, the presence of higher PGDS excretion independently associated with history of CVD (p = 0.025, OR= 3.847, CI 1.180-12.545).
Conclusions: In type 2 diabetes patients, the elevation of urinary PGDS secretion closely associated with cardiovascular events and may be a supplemental or additional marker to the criteria of metabolic syndrome. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2006.09.004

Re-evaluation of waist circumference in metabolic syndrome: A comparison between Japanese men and women 査読

Nobuyuki Miyatake, Jun Wada, Sumiko Matsumoto, Hidetaka Nishikawa, Hirofumi Makino, Takeyuki Numata

ACTA MEDICA OKAYAMA 61 ( 3 ) 167 - 169 2007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：OKAYAMA UNIV MED SCHOOL

We re-evaluated the criteria for waist circumference to predict the accumulation of the components of metabolic syndrome. We used data for 3,185 Japanese, aged 20-79 years. Metabolic syndrome has recently been redefined by a new criterion in Japan, in which waist circumference cutoff points, i.e. 85 cm for men and 90 cm for women, are employed. Among the 3,185 Japanese considered in the present study, 335 men (26.8%) and 69 women (3.6%) were diagnosed as having metabolic syndrome. A cutoff point as a predictor for 2 or more components of metabolic syndrome was evaluated by sensitivity/specificity and a receiver operating characteristic (ROC) curve. The optimal point was estimated as being approximately 85 cm of waist circumference in men and 75 cm in women. We therefore recommend a cutoff value, 75 cm of waist circumference, for the criterion of metabolic syndrome in women.

DOI： 10.18926/AMO/32900

The Role for HNF-1 beta-Targeted Collectrin in Maintenance of Primary Cilia and Cell Polarity in Collecting Duct Cells 査読

Yanling Zhang, Jun Wada, Akihiro Yasuhara, Izumi Iseda, Jun Eguchi, Kenji Fukui, Qin Yang, Kazuya Yamagata, Thomas Hiesberger, Peter Igarashi, Hong Zhang, Haiyan Wang, Shigeru Akagi, Yashpal S. Kanwar, Hirofumi Makino

PLOS ONE 2 ( 5 ) 2007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：PUBLIC LIBRARY SCIENCE

Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1 alpha, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1 beta and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to gamma-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1 beta and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1 beta regulated genes.

DOI： 10.1371/journal.pone.0000414

Comparison of muscle strength between Japanese men with and without metabolic syndrome 査読

Nobuyuki Miyatake, Jun Wada, Takeshi Saito, Hidetaka Nishikawa, Sumiko Matsumoto, Motohiko Miyachi, Hirofumi Makino, Takeyuki Numata

ACTA MEDICA OKAYAMA 61 ( 2 ) 99 - 102 2007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：OKAYAMA UNIV MED SCHOOL

We compared muscle strength between Japanese men with and without metabolic syndrome. We used data for 323 Japanese men with metabolic syndrome and 893 Japanese men without the syndrome. Metabolic syndrome was defined by a new criterion in Japan, and the parameters for muscle strength, i.e. grip strength, leg strength were measured. Leg strength was found to be significantly higher in subjects with metabolic syndrome than in those without, while muscle strength per body weight was significantly lower in subjects with the syndrome. Lower muscle strength per body weight may be one of the characteristic features in subjects with metabolic syndrome.

Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappa B activation 査読

Sakiko Ohga, Kenichi Shikata, Kosuke Yozai, Shinichi Okada, Daisuke Ogawa, Hitomi Usui, Jun Wada, Yasushi Shikata, Hirofumi Makino

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 292 ( 4 ) F1141 - F1150 2007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：AMER PHYSIOLOGICAL SOC

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM + pio). Diabetes was induced by injection with streptozotocin (STZ). The DM + pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-beta, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-kappa B activity was increased in diabetic rats and reduced by pioglitazone. PPAR-gamma was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-kappa B in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-kappa B. However, pioglitazone did not show the changes in the presence of PPAR-kappa B antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-kappa B activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.

DOI： 10.1152/ajprenal.00288.2005

Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation 査読

Sakiko Ohga, Kenichi Shikata, Kosuke Yozai, Shinichi Okada, Daisuke Ogawa, Hitomi Usui, Jun Wada, Yasushi Shikata, Hirofumi Makino

American Journal of Physiology - Renal Physiology 292 ( 4 ) F1141 - F1150 2007年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM+pio). Diabetes was induced by injection with streptozotocin (STZ). The DM+pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-β, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-κB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-γ was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. Highglucose conditions increased the expression of ICAM-1 and the activation of NF-κB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-κB. However, pioglitazone did not show the changes in the presence of PPAR-γ antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney. Copyright © 2007 the American Physiological Society.

DOI： 10.1152/ajprenal.00288.2005

Changes of gene expression profiles in macrophages stimulated by angiotensin II - Angiotensin II induces MCP-2 through AT(1)-receptor 査読

Atsuhito Tone, Kenichi Shikata, Daisuke Ogawa, Sakiko Sasaki, Ryo Nagase, Motofumi Sasaki, Kosuke Yozai, Hitomi Kataoka Usui, Shinichi Okada, Jun Wada, Yasushi Shikata, Hirofumi Makino

JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM 8 ( 1 ) 45 - 50 2007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：SAGE PUBLICATIONS LTD

Introduction. Macrophages play critical roles in the development of atherosclerosis and diabetic nephropathy as well as many inflammatory diseases. Angiotensin II type 1 receptor antagonists (AIIA) are beneficial for the prevention of atherosclerosis and diabetic nephropathy suggesting that angiotensin II (Ang II) promotes the development of these diseases. it has recently been reported that Ang II exerts proinflammatory actions in vivo and in vitro. This study was aimed to clarify the direct effects of Ang II on monocytes/macrophages.
Materials and methods. PMA-treatedTHP-1 cells, a human monocytic leukaemia cell line, were treated with Ang II (10(-6) mol/L) for 24 hours with or without AIIA (CV11974). We evaluated gene expression profiles of these cells using DNA microarray system and quantified them by real-time RT-PCR.
Results. DNA microarray revealed that in total 19 genes, including monocyte chemoattractant protein (MCP)-2, were up-regulated by Ang II and down-regulated by AIIA. Real-time RT-PCR showed that up-regulation of MCP-2 with Ang II is blocked by the ARA (CV11974) but not by an AT(2)-receptor antagonist.
Conclusions. These results suggest that Ang II directly stimulates MCP-2 expression through AT(1)-receptors in activated macrophages. Ang II may contribute to the persistence or amplification of microinflammation in vessel walls, heart and kidney. Vasculoprotective or renoprotective effects of ARA might partly depend on direct anti-inflammatory effects on macrophages.

DOI： 10.3317/jraas.2007.007

Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity 査読

Atsushi Tanabe, Takahiro Yanagiya, Aritoshi Iida, Susumu Saito, Akihiro Sekine, Atsushi Takahashi, Takahiro Nakamura, Tatsuhiko Tsunoda, Seika Kamohara, Yoshio Nakata, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Kazuyuki Hamaguchi, Tatsuo Shimada, Kiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Toshiie Sakata, Yuji Matsuzawa, Naoyuki Kamatani, Yusuke Nakamura, Kikuko Hotta

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 92 ( 3 ) 1145 - 1154 2007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：ENDOCRINE SOC

Context: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear.
Objective: Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms ( SNPs).
Design and Setting: We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P <= 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied.
Patients: Obese subjects ( body mass index >= 30 kg/m(2), n = 890) and control subjects ( general population; n = 658, body mass index <= 25kg/m(2); n = 711) were recruited for this study.
Results: Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity ( odds ratio, 9.23; 95% confidence interval, 2.77 - 30.80; chi(2) = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides.
Conclusions: Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.

DOI： 10.1210/jc.2006-1808

Macrophage scavenger receptor-A-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation 査読

Hitorni Kataoka Usui, Kenichi Shikata, Motofurni Sasaki, Shinichi Okada, Mitsuhiro Matsuda, Yasushi Shikata, Daisuke Ogawa, Yuichi Kido, Ryo Nagase, Kosuke Yozai, Sakiko Ohga, Atsuhito Tone, Jun Wada, Masahiro Takeya, Seikoh Horiuchi, Tatsuhiko Kodama, Hirofunti Makino

DIABETES 56 ( 2 ) 363 - 372 2007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：AMER DIABETES ASSOC

Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A(-/-)) mice. Diabetes was induced in SR-A(-/-) and wild-type (SRA(+/+)) mice by streptozotocin injection. Diabetic SR-A(+/+) mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-P at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A(-/-) mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A(-/-) mice compared with diabetic SR-A(+/+) mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A(+/+) mice and suppressed in diabetic SR-A(-/-) mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.

DOI： 10.2337/db06-0359

Serpins and the metabolic syndrome 査読

Jun Wada

Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity 411 - 423 2007年1月

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