Faculty Profiles - WADA Jun

Papers - WADA Jun

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[Chronic kidney disease].

Katayama, A., Wada, J., Makino, H.

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1 2011

[Chemerin, RBP4 and vaspin].

Wada, J., Teshigawara, S., Nakatsuka, A.

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1 2011

Insufficient control of morning home blood pressure in Japanese patients with hypertension associated with diabetes mellitus Reviewed

Haruhito A. Uchida, Yoshio Nakamura, Hisanao Norii, Masanobu Kaihara, Yoshihisa Hanayama, Ken-Ei Sada, Jun Wada, Kenichi Shikata, Hirofumi Makino

JOURNAL OF DIABETES INVESTIGATION 1 ( 6 ) 266 - 272 2010.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Aims/Introduction: The combination of hypertension with diabetes mellitus (DM) has been recognized as a critical risk factor for cardiovascular disease (CVD). We investigated the blood pressure levels in hypertensive patients with DM (HDM patients) compared with those without DM (HnDM patients). Furthermore, we examined the effect of risk factors, including chronic kidney disease (CKD) and stroke, on the management of both office blood pressure (OBP) and morning home blood pressure (MHBP).
Materials and Methods: OBP and MHBP were evaluated in 1230 essential hypertensive patients in 30 institutions. Among them, 366 (30%) were complicated with DM.
Results: The ratio of masked hypertensives whose systolic OBP was < 140 mmHg and systolic MHBP was more than 135 mmHg in HDM patients was significantly higher than that in HnDM patients (P < 0.02). HDM patients had significantly lower systolic and diastolic OBP and diastolic MHBP than HnDM patients (P < 0.05, respectively). However, systolic MHBP in HDM patients tended to be higher compared with HnDM patients (P = 0.0623). A stratified analysis showed that HDM patients with CKD or stroke had significantly higher systolic MHBP than others (P < 0.05, respectively). The adjusted odds ratio for morning hypertension defined by a systolic MHBP more than 135 mmHg was significantly higher in the HDM patients with CKD (1.98) compared with HnDM patients without CKD (reference).
Conclusions: Diabetes, CKD and stroke are risk factors for MHBP. More intensive treatment is needed to achieve the therapeutic goal for systolic MHBP in HDM patients, especially those who are complicated with CKD or stroke. (J Diabetes Invest, doi:10.1111/j.2040-1124.2010.00056.x, 2010).

DOI： 10.1111/j.2040-1124.2010.00056.x

Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population Reviewed

Kikuko Hotta, Michihiro Nakamura, Takahiro Nakamura, Tomoaki Matsuo, Yoshio Nakata, Seika Kamohara, Nobuyuki Miyatake, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Masato Yoneda, Atsushi Nakajima, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Manabu Kawamoto, Hiroaki Masuzaki, Takato Ueno, Kazuyuki Hamaguchi, Kiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Kazuwa Nakao, Toshiie Sakata, Yuji Matsuzawa, Yusuke Nakamura, Naoyuki Kamatani

JOURNAL OF HUMAN GENETICS 55 ( 11 ) 738 - 742 2010.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist-hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist-hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2 beta (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P=0.0039 and 0.0039, respectively), SFA (P=0.0027 and 0.0023, respectively) and VFA (P=0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects. Journal of Human Genetics (2010) 55, 738-742; doi:10.1038/jhg.2010.99; published online 12 August 2010

DOI： 10.1038/jhg.2010.99

Peramivir for Severe Influenza Infection in a Patient with Diabetic Nephropathy Reviewed

Tatsuyo Nasu, Daisuke Ogawa, Jun Wada, Hirofumi Makino

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 182 ( 9 ) 1209 - 1210 2010.11

In Vivo Delivery of Gremlin siRNA Plasmid Reveals Therapeutic Potential against Diabetic Nephropathy by Recovering Bone Morphogenetic Protein-7 Reviewed

Qingxian Zhang, Yonghong Shi, Jun Wada, Sandra M. Malakauskas, Maodong Liu, Yunzhuo Ren, Chunyang Du, Huijun Duan, Yingmin Li, Ying Li, Yanling Zhang

PLOS ONE 5 ( 7 ) 2010.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor-beta 1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy.

DOI： 10.1371/journal.pone.0011709

Comparison of Insulin Detemir and Insulin Glargine on Glycemic Variability in Patients with Type 1 and Type 2 Diabetes Reviewed

A. Tone, I. Iseda, C. Higuchi, K. Tsukamoto, A. Katayama, Y. Matsushita, K. Hida, J. Wada, K. Shikata

EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES 118 ( 5 ) 320 - 324 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH

Aims: To compare the glycemic variability of insulin detemir and insulin glargine in type 1 and type 2 diabetic patients.
Methods: 15 type 1 and 14 type 2 diabetic patients receiving intensive insulin therapy with insulin glargine were enrolled. Before and after switching insulin glargine to insulin detemir, we assessed fasting glucose variability using the standard deviation (SD) and the coefficient of variance (CV) of self-monitored fasting blood sugar (FBS) levels.
Results: The SD and CV values were significantly decreased in type 1 diabetes after switching the therapy, though there was no significant difference in type 2 diabetes. The frequency of hypoglycemia was decreased in type 1 diabetes and there was no change in type 2 diabetes. The changes of the CV value also showed significant positive correlation with fasting serum CPR levels in all patients and total insulin dose in type 1 diabetes. The changes of frequency of hypoglycemia showed significant positive correlation with total and basal insulin dose adjusted for body weight in type 1 diabetes.
Conclusion: The present study demonstrated lower within-subject variability of insulin detemir compared to insulin glargine, suggesting that the basal insulin replacement with insulin detemir may provide a useful therapeutic strategy for uncontrolled type 1 diabetes with high glucose variability.

DOI： 10.1055/s-0029-1243230

Effects of icodextrin peritoneal dialysis solution on the peritoneal membrane in the STZ-induced diabetic rat model with partial nephrectomy Reviewed

Ai Nakao, Kazushi Nakao, Yuji Takatori, Syoichirou Kojo, Junko Inoue, Shigeru Akagi, Hitoshi Sugiyama, Jun Wada, Hirofumi Makino

NEPHROLOGY DIALYSIS TRANSPLANTATION 25 ( 5 ) 1479 - 1488 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Methods. Thirty-two male Wistar rats were divided into four groups: control Wistar rats with non-treated (n = 8), streptozotocin (STZ)-induced diabetic rats with 5/6 kidney ablation (n = 8), STZ-induced diabetic rats with 5/6 kidney ablation injected with a standard lactate-buffered 4.25% glucose-based PDF (Dianeal (R); n = 8) and STZ-induced diabetic rats with 5/6 kidney ablation injected with 7.5% icodextrin-based PDF (Extraneal (R); n = 8). Intraperitoneal injection was performed once daily with an instillation volume of 20 ml per injection during 8 weeks.
Results. Chronic high-glucose-based PDF exposure resulted in increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expression, accumulation of advanced glycation end-products (AGEs), and up-regulation of the receptor for AGE (RAGE), which were ameliorated in the icodextrin-based PDF group. The peritoneal damages, such as neoangiogenesis and submesothelial fibrosis, were significantly reduced in icodextrin-based PDF compared to high-glucose-based PDF.
Conclusions. Long-term in vivo exposure to high glucose-based PDF promotes the fibrosing process of peritoneal membranes. Icodextrin-based PDF may be helpful in slowing the PDF-induced deterioration of peritoneal function and prolonging the use of peritoneal dialysis in patients with diabetes.

DOI： 10.1093/ndt/gfp479

The Usefulness of Super-Selective Computed Tomography Angiography (CTA) for Diagnosing and Localizing a Small Insulinoma Reviewed

Akihiro Katayama, Izumi Iseda, Atsuhito Tone, Yuichi Matsushita, Kentaro Inoue, Keiko Tsukamoto, Haruhiro Yamashita, Ichiro Yamadori, Jun Wada, Kazuyuki Hida

INTERNAL MEDICINE 49 ( 18 ) 1983 - 1986 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

Localization of insulinomas by preoperative imaging is critical for successful surgical resection. However, the visualization and localization of small insulinomas by recent imaging modalities still remains a challenge. Here, we report a 77-year-old woman with a small insulinoma successfully localized by performing arterial stimulation and venous sampling (ASVS), and subsequent super-selective CTA (SSCTA). It was not visualized by routine non-invasive imaging tests such as digital subtraction angiography (DSA). The small size (1.0 cm) of the surgically removed tumor supports the usefulness of SSCTA for localizing very small insulinomas.

DOI： 10.2169/internalmedicine.49.3739

Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population Reviewed

Kikuko Hotta, Michihiro Nakamura, Takahiro Nakamura, Tomoaki Matsuo, Yoshio Nakata, Seika Kamohara, Nobuyuki Miyatake, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Hiroaki Masuzaki, Masato Yoneda, Atsushi Nakajima, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Manabu Kawamoto, Takato Ueno, Kazuyuki Hamaguchi, Kiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Kazuwa Nakao, Toshiie Sakata, Yuji Matsuzawa, Naoyuki Kamatani, Yusuke Nakamura

JOURNAL OF HUMAN GENETICS 54 ( 12 ) 727 - 731 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

There is evidence that the obesity phenotype in the Caucasian populations is associated with variations in several genes, including neuronal growth regulator 1 (NEGR1), SEC16 homolog B (SCE16B), transmembrane protein 18 (TMEM18), ets variant 5 (ETV5), glucosamine-6-phosphate deaminase 2 (GNPDA2), prolactin (PRL), brain-derived neurotrophic factor (BDNF), mitochondrial carrier homolog 2 (MTCH2), Fas apoptotic inhibitory molecule 2 (FAIM2), SH2B adaptor protein 1 (SH2B1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15). To investigate the relationship between obesity and these genes in the Japanese population, we genotyped 27 single-nucleotide polymorphisms (SNPs) in 14 genes from obese subjects (n=1129, body mass index (BMI) >= 30 kg m(-2)) and normal-weight control subjects (n=1736, BMI <25 kg m(-2)). The SNP rs10913469 in SEC16B (P=0.000012) and four SNPs (rs2867125, rs6548238, rs4854344 and rs7561317) in the TMEM18 gene (P=0.00015), all of which were in almost absolute linkage disequilibrium, were significantly associated with obesity in the Japanese population. SNPs in GNPDA2, BDNF, FAIM2 and MC4R genes were marginally associated with obesity (P<0.05). Our data suggest that some SNPs identified by genome-wide association studies in the Caucasians also confer susceptibility to obesity in Japanese subjects. Journal of Human Genetics (2009) 54, 727-731; doi: 10.1038/jhg.2009.106; published online 23 October 2009

DOI： 10.1038/jhg.2009.106

Endothelial barrier protection by FTY720 under hyperglycemic condition: involvement of focal adhesion kinase, small GTPases, and adherens junction proteins Reviewed

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

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 297 ( 4 ) C945 - C954 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Sarai K, Shikata K, Shikata Y, Omori K, Watanabe N, Sasaki M, Nishishita S, Wada J, Goda N, Kataoka N, Makino H. Endothelial barrier protection by FTY720 under hyperglycemic condition: involvement of focal adhesion kinase, small GTPases, and adherens junction proteins. Am J Physiol Cell Physiol 297: C945-C954, 2009. First published August 5, 2009; doi:10.1152/ajpcell.00606.2008.-Recently, sphingosine 1-phosphate (S1P) has been highlighted as an endothelial barrier-stabilizing mediator. FTY720 is a S1P analog originally developed as a novel immunosuppressant. The phosphorylated form of FTY720 binds to S1P receptors to exert S1P-like biological effects, suggesting endothelial barrier promotion by FTY720. To elucidate whether FTY720 induces signaling events related to endothelial barrier enhancement under hyperglycemic conditions, human microvascular endothelial cells (HMVECs) preincubated with hyperglycemic (30 mM) medium were treated with 100 nM FTY720 for 3 h. Immunofluorescent microscopy and coprecipitation study revealed FTY720-induced focal adhesion kinase (FAK)-associated adherens junction (AJ) assembly at cell-cell contacts coincident with formation of a prominent cortical actin ring. FTY720 also induced transmonolayer electrical resistance (TER) augmentation in HMVEC monolayers in both normoglycemic and hyperglycemic conditions, implying endothelial barrier enhancement. Similar to S1P, site-specific FAK tyrosine phosphorylation analysis revealed FTY720-induced FAK [Y(576)] phosphorylation without phosphorylation of FAK [Y(397)/Y(925)]. Furthermore, FTY720 conditioned the phosphorylation profile of FAK [Y(397)/Y(576)/Y(925)] in hyperglycemic medium to the same pattern observed in normoglycemic medium. FTY720 challenge resulted in small GTPase Rac activation under hyperglycemic conditions, whereas increased Rho activity in hyperglycemic medium was restored to the basal level. Rac protein depletion by small interfering RNA (siRNA) technique completely abolished FTY720-induced FAK [Y(576)] phosphorylation. These findings strongly suggest the barrier protective effect of FTY720 on HMVEC monolayers in hyperglycemic medium via S1P signaling, further implying the possibility of FTY720 as a therapeutic agent of diabetic vascular disorder.

DOI： 10.1152/ajpcell.00606.2008

Historical chronology of basic and clinical research in diabetic nephropathy and contributions of Japanese scientists Reviewed

Jun Wada, Hirofumi Makino

CLINICAL AND EXPERIMENTAL NEPHROLOGY 13 ( 5 ) 405 - 414 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The most problematic issue in clinical nephrology worldwide is the relentless and progressive increase in patients with end-stage renal disease (ESRD). Diabetic nephropathy has considerable impact on society in the areas of public health and social economy; many scientists are involved in research for the elucidation of the pathogenesis of diabetic nephropathy and for the prevention and cure of the disease. In contrast, diabetic nephropathy was a neglected or ignored disease in the historical era, and few dedicated physicians recognized the disease process of diabetic nephropathy. In this review, we look back on the history of basic and clinical research on diabetic nephropathy and survey the recent progress of the research, especially focusing on the contribution of Japanese scientists.

DOI： 10.1007/s10157-009-0175-5

Enhanced interaction between focal adhesion and adherens junction proteins: Involvement in sphingosine 1-phosphate-induced endothelial barrier enhancement Reviewed

Xiaoguang Sun, Yasushi Shikata, Lichun Wang, Kazuyoshi Ohmori, Naoko Watanabe, Jun Wada, Kenichi Shikata, Konstantin G. Birukov, Hirofumi Makino, Jeffrey R. Jacobson, Steven M. Dudek, Joe G. N. Garcia

MICROVASCULAR RESEARCH 77 ( 3 ) 304 - 313 2009.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Sphingosine 1-phosphate (S1P) is an important vascular barrier regulatory agonist which enhances the junctional integrity of human lung endothelial cell monolayers. We have now demonstrated that S1P induced cortical actin ring formation and redistribution of focal adhesion kinase (FAK) and paxillin to the cell periphery suggesting the critical role of cell-cell adhesion in endothelial barrier enhancement. Co-immunoprecipitation studies revealed increased association of VE-cadherin with FAK and paxillin in S1P-challenged human pulmonary artery endothelial cell (HPAEC) monolayers. Furthermore, SIP-induced enhancement of VE-cadherin interaction with alpha-catenin and beta-catenin was associated with the increased formation of FAK-beta-catenin protein complexes. Depletion of beta-catenin (siRNA) resulted in loss of S1P-mediated VE-cadherin association with FAK and paxillin rearrangement. Furthermore, transendothelial electrical resistance (an index of barrier function) demonstrated that beta-catenin siRNA significantly attenuated S1P-induced barrier enhancement. These results demonstrate a mechanism of S1P-induced endothelial barrier enhancement via beta-catenin-linked adherens junction and focal adhesion interaction. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.mvr.2008.12.004

Screening of 336 single-nucleotide polymorphisms in 85 obesity-related genes revealed McKusick-Kaufman syndrome gene variants are associated with metabolic syndrome Reviewed

Kikuko Hotta, Takahiro Nakamura, Junichi Takasaki, Hiroshi Takahashi, Atsushi Takahashi, Yoshio Nakata, Seika Kamohara, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Hiroaki Masuzaki, Masato Yoneda, Atsushi Nakajima, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Kazuyuki Hamaguchi, Kiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Kazuwa Nakao, Toshiie Sakata, Yuji Matsuzawa, Naoyuki Kamatani, Yusuke Nakamura

JOURNAL OF HUMAN GENETICS 54 ( 4 ) 230 - 235 2009.4

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Genetic factors are important in the development of metabolic syndrome. However, the genetic background of metabolic syndrome remains unclear. We screened polymorphisms in 85 obesity-related genes to determine which may be associated with metabolic syndrome. A total of 336 single-nucleotide polymorphisms (SNPs) in 85 genes selected from the JSNP database were genotyped. We conducted case-control association analyses using patients with metabolic syndrome (n=1080) and control individuals (n=528) who had no risk of the metabolic syndrome. Three SNPs in the McKusick-Kaufman syndrome (MKKS) gene were significantly related to metabolic syndrome by case-control association study; rs1545 (odds ratio (OR) adjusted for age and gender, 1.45; 95% confidence interval (CI), 1.21-1.74; P = 0.000043 (additive model)); rs1547 (OR, 1.45; 95% CI, 1.21-1.74; P=0.000041); and rs2294901 (OR, 1.46; 95% CI, 1.22-1.75; P=0.000033). We selected five tag SNPs (rs2294901, rs221667, rs6133922, rs6077785 and rs6108572) in the MKKS gene. They were in one linkage disequilibrium (LD) block and rs6133922 (P=0.00042), rs6077785 (P=0.000013) and rs6108572 (P=0.000019) as well as rs2294901 were significantly associated with metabolic syndrome. TGAAA haplotype was protective against the metabolic syndrome (P=0.0074), and CCGTT haplotype was susceptible (P=0.00070) to the metabolic syndrome. Our data suggest that genetic variations at MKKS gene influence the risk of metabolic syndrome. Journal of Human Genetics (2009) 54, 230-235; doi: 10.1038/jhg.2009.16; published online 27 February 2009

DOI： 10.1038/jhg.2009.16

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction Reviewed

Lin Sun, Ping Xie, Jun Wada, Naoki Kashihara, Fu-you Liu, Yanan Zhao, Deepak Kumar, Sumant S. Chugh, Farhad R. Danesh, Yashpal S. Kanwar

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 19 ( 12 ) 2293 - 2301 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC NEPHROLOGY

The role of tubular injury in diabetic nephropathy is relatively unknown, despite that apoptosis of tubular epithelial cells is commonly observed in human renal biopsies. The GTPase Ras-proximate-1 (Rap1b) is upregulated in the hyperglycemic state and is known to increase B-Raf, an antiapoptotic effector protein. In this study, the effects of high glucose on renal tubular apoptosis and the potential ability for Rap1b to ameliorate these effects were investigated. In the kidneys of diabetic mice, apoptotic tubular cells and dysmorphic mitochondria were observed, Bcl-2 expression was decreased, and Bax expression was increased. Total Rap1b expression was slightly increased, but its associated GTPase activity was significantly decreased. In vitro, high extracellular glucose led to decreased Bcl-2 expression, reduced Rap1b GTPase activity, and increased levels of both Bax and GTPase activating protein in a proximal tubular cell line (HK-2). These changes were accompanied by increased DNA fragmentation, decreased high molecular weight mitochondrial DNA, altered mitochondrial morphology and function, disrupted Bcl-2-Bax and Bcl-2-Rap1b interactions, and reduced cell survival. Overexpression of Rap1b partially prevents these abnormalities. Furthermore, the BH4 domain of Bcl-2 was found to be required for successful protein-protein interaction between Bcl-2 and Rap1b. In summary, these data suggest that Rap1b ameliorates glucose-induced mitochondrial dysfunction in renal tubular cells.

DOI： 10.1681/ASN.2008030336

Bilateral dystonia in type 1 diabetes: A case report Reviewed

Akihiro Yasuhara, Jun Wada, Hirofumi Makino

Journal of Medical Case Reports 2 352 2008.11

Language：English Publishing type：Research paper (scientific journal)

Introduction: Diabetic hemichorea-hemiballismus is a rare complication of type 2 diabetes. Here, we report a case with type 1 diabetes, with hemichorea and bilateral dystonia manifested as hyperglycemia-induced involuntary movement. Case presentation: A 62-year-old Japanese women with body weight loss of 30 kg during the past year developed symptoms of thirst, polydipsia and polyuria. She also presented with hemichorea and bilateral dystonia for 5 days and extremely high plasma glucose (774 mg/dl), hemoglobin A1c (21.2%) and glycated albumin (100%) with ketosis. Based on the presence of glutamic acid decarboxylase antibodies (18,000 U/ml
normal &lt
1.3 U/ ml), low daily urinary excretion of C-peptide (7.8 μg), ketosis and human leucocyte antigen typing DR-4, we diagnosed type 1 diabetes mellitus. We treated the patient with a continuous intravenous regular insulin infusion and medication with haloperidol, and dystonia completely disappeared within 3 days. Conclusion: Hyperglycemia-induced involuntary movement is one of the manifestations of dystonia and hemichorea-hemiballism. © 2008 Yasuhara et al
licensee BioMed Central Ltd.

DOI： 10.1186/1752-1947-2-352

Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide-Sensitive Factor Attachment Protein Receptor Complex Reviewed

Akihiro Yasuhara, Jun Wada, Sandra M. Malakauskas, Yanling Zhang, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Sanae Teshigawara, Kazuya Yamagata, Thu H. Le, Hirofumi Makino

CIRCULATION 118 ( 21 ) 2146 - 2155 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background-Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1 alpha and-1 beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins.
Methods and Results-Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 mu mol/L aldosterone in mIMCD-3 cells.
Conclusions-Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension. (Circulation. 2008; 118: 2146-2155.)

DOI： 10.1161/CIRCULATIONAHA.108.787259

INSIG2 gene rs7566605 polymorphism is associated with severe obesity in Japanese Reviewed

Kikuko Hotta, Michihiro Nakamura, Yoshio Nakata, Tomoaki Matsuo, Seika Kamohara, 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, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Kazuwa Nakao, Toshiie Sakata, Yuji Matsuzawa, Kiyoji Tanaka, Naoyuki Kamatani, Yusuke Nakamura

JOURNAL OF HUMAN GENETICS 53 ( 9 ) 857 - 862 2008.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The single nucleotide polymorphism (SNP) rs7566605 in the upstream region of the insulin-induced gene 2 (INSIG2) is associated with the obesity phenotype in many Caucasian populations. In Japanese, this association with the obesity phenotype is not clear. To investigate the relationship between rs7566605 and obesity in Japanese, we genotyped rs7566605 from severely obese subjects [n = 908, body mass index (BMI) >= 30 kg/m(2)] and normal-weight control subjects (n = 1495, BMI < 25 kg/m(2)). A case-control association analysis revealed that rs7566605 was significantly associated with obesity in Japanese. The P value in the minor allele recessive mode was 0.00020, and the odds ratio (OR) adjusted for gender and age was 1.61 [95% confidential interval (CI) = 1.24-2.09]. Obesity-associated phenotypes, which included the level of BMI, plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure, were not associated with the rs7566605 genotype. Thus, rs7566605 in the upstream region of the INSIG2 gene was found to be associated with obesity, i.e., severe obesity, in Japanese.

DOI： 10.1007/s10038-008-0317-8

Variations in the FTO gene are associated with severe obesity in the Japanese Reviewed

Kikuko Hotta, Yoshio Nakata, Tomoaki Matsuo, Seika Kamohara, 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, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Kazuwa Nakao, Toshiie Sakata, Yuji Matsuzawa, Kiyoji Tanaka, Naoyuki Kamatani, Yusuke Nakamura

JOURNAL OF HUMAN GENETICS 53 ( 6 ) 546 - 553 2008.6

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Variations in the fat-mass and obesity-associated gene (FTO) are associated with the obesity phenotype in many Caucasian populations. This association with the obesity phenotype is not clear in the Japanese. To investigate the relationship between the FTO gene and obesity in the Japanese, we genotyped single nucleotide polymorphisms (SNPs) in the FTO genes from severely obese subjects [n = 927, body mass index (BMI) >= 30 kg/m(2)] and normal-weight control subjects (n = 1,527, BMI < 25 kg/m(2)). A case-control association analysis revealed that 15 SNPs, including rs9939609 and rs1121980, in a linkage disequilibrium (LD) block of approximately 50 kb demonstrated significant associations with obesity; rs1558902 was most significantly associated with obesity. P value in additive mode was 0.0000041, and odds ratio (OR) adjusted for age and gender was 1.41 [95% confidential interval (CI) = 1.22-1.62]. Obesity-associated phenotypes, which include the level of plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure were not associated with the rs1558902 genotype. Thus, the SNPs in the FTO gene were found to be associated with obesity, i.e., severe obesity, in the Japanese.

DOI： 10.1007/s10038-008-0283-1

Glycated albumin levels predict long-term survival in diabetic patients undergoing haemodialysis Reviewed

Kousuke Fukuoka, Kazushi Nakao, Hisanori Morimoto, Ai Nakao, Yuji Takatori, Katsuhiko Arimoto, Masafumi Taki, Jun Wada, Hirofumi Makino

NEPHROLOGY 13 ( 4 ) 278 - 283 2008.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Aim: Glycated albumin (GA) is recognized as a reliable marker for monitoring glycemic control particularly in patients with end-stage renal disease (ESRD). Here, we investigated the impact of GA levels on long-term survival in diabetic patients with ESRD.
Methods: We enrolled ESRD patients with diabetic nephropathy into our single-centre prospective follow-up study (n = 98, 66 men and 32 women; age 68.2 +/- 12.3 years) with a mean follow-up period of 47.7 months. All patients had started haemodialysis between December 1992 and November 2003. They were categorized into two groups according to their GA levels at the initiation of haemodialysis; GA < 29% (low-GA group; n = 54) and GA >= 29% (high-GA group; n = 44).
Results: Between low-GA and high-GA groups, there were no significant differences in various clinical parameters except GA and HbA1c levels. The cumulative survival rate of low-GA group was significantly higher than that of high-GA group (P = 0.034, log-rank test). After adjustment for age, sex, total cholesterol, C-reactive protein and albumin, high-GA was a significant predictor of survival (hazard ratio 1.042 per 1.0% increment of GA, 95% Cl 1.014-1.070, P < 0.05), but not in the case with HbA1c. Cox proportional hazard model demonstrated that high-GA group was a significant predictor for cardiovascular death (hazard ratio 2.971 (1.064-8.298), P = 0.038).
Conclusion: We conclude that poor glycemic control (GA >= 29%) before starting haemodialysis is associated with increased cardiovascular morbidity and shortened survival in diabetic patients with ESRD.

DOI： 10.1111/j.1440-1797.2007.00864.x

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