Faculty Profiles - WADA Jun

Papers - WADA Jun

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Impact of circulating vaspin levels on metabolic variables in elderly twins Reviewed

K. Hida, P. Poulsen, S. Teshigawara, E. Nilsson, M. Friedrichsen, R. Ribel-Madsen, L. Grunnet, S. S. Lund, J. Wada, A. Vaag

DIABETOLOGIA 55 ( 2 ) 530 - 532 2012.2

Galectin-9 and T Cell Immunoglobulin Mucin-3 Pathway Is a Therapeutic Target for Type 1 Diabetes Reviewed

Motoko Kanzaki, Jun Wada, Koichi Sugiyama, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Jun Eguchi, Hisaya Akiba, Hideo Yagita, Hirofumi Makino

ENDOCRINOLOGY 153 ( 2 ) 612 - 620 2012.2

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

Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-alpha, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-gamma in MIN6 cells, and Gal-9 was also expressed in the pancreatic beta-cells in NOD mice, suggesting Gal-9 may be released from pancreatic beta-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 mu M, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-alpha production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-alpha production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-alpha production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes. (Endocrinology 153: 612-620, 2012)

DOI： 10.1210/en.2011-1579

Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women Reviewed

Kikuko Hotta, Aya Kitamoto, Takuya Kitamoto, Seiho Mizusawa, Hajime Teranishi, Tomoaki Matsuo, Yoshio Nakata, Hideyuki Hyogo, Hidenori Ochi, Takahiro Nakamura, Seika Kamohara, Nobuyuki Miyatake, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Masato Yoneda, Atsushi Nakajima, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Hiroaki Masuzaki, Takato Ueno, Kazuaki Chayama, Kazuyuki Hamaguchi, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Toshiie Sakata, Kiyoji Tanaka, Yuji Matsuzawa, Kazuwa Nakao, Akihiro Sekine

JOURNAL OF HUMAN GENETICS 57 ( 1 ) 46 - 51 2012.1

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

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women. Journal of Human Genetics (2012) 57, 46-51; doi: 10.1038/jhg.2011.127; published online 10 November 2011

DOI： 10.1038/jhg.2011.127

The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome: a randomized controlled trial Reviewed

Jun Wada

International Journal of Nephrology and Renovascular Disease 5 91 - 6 2012

A Case of Type 2 Diabetes and Metastatic Liver Cancer Exhibiting Hypercholesterolemia with Abnormal Lipoproteins Reviewed

Motoko Kanzaki, Jun Wada, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Junichiro Nasu, Kazuhide Yamamoto, Hirofumi Makino

INTERNAL MEDICINE 51 ( 6 ) 619 - 623 2012

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

Although the appearance of abnormal lipoproteins in liver diseases is well known, the precise analyses of abnormal lipoproteins remain elusive. Here, we report a 71-year-old woman with type 2 diabetes whose serum cholesterol levels were elevated to 560 mg/dL over a 4-month period. High-performance liquid chromatography demonstrated the presence of lipoprotein-X and lipoprotein-Y and sigmoid colon cancer and multiple liver metastases were found by colonoscopy and computed tomography. Remission of the primary colon cancer and liver lesions was achieved by chemotherapy with oxaliplatin and fluorouracil and her serum cholesterol went back to basal levels associated with the disappearance of abnormal lipoproteins.

DOI： 10.2169/internalmedicine.51.6486

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in db/db Mice Reviewed

Chikage Sato-Horiguchi, Daisuke Ogawa, Jun Wada, Hiromi Tachibana, Ryo Kodera, Jun Eguchi, Atsuko Nakatsuka, Naoto Terami, Kenichi Shikata, Hirofumi Makino

NEPHRON EXPERIMENTAL NEPHROLOGY 121 ( 3-4 ) E97 - E108 2012

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

Background/Aims: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. Methods: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. Results: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-beta) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. Conclusions: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress. Copyright (c) 2013 S. Karger AG, Basel

DOI： 10.1159/000343102

Computed tomography analysis of the association between the SH2B1 rs7498665 single-nucleotide polymorphism and visceral fat area Reviewed

Kikuko Hotta, Takuya Kitamoto, Aya Kitamoto, Seiho Mizusawa, Tomoaki Matsuo, Yoshio Nakata, Hideyuki Hyogo, Hidenori Ochi, Seika Kamohara, Nobuyuki Miyatake, Kazuaki Kotani, Ryoya Komatsu, Naoto Itoh, Ikuo Mineo, Jun Wada, Masato Yoneda, Atsushi Nakajima, Tohru Funahashi, Shigeru Miyazaki, Katsuto Tokunaga, Hiroaki Masuzaki, Takato Ueno, Kazuaki Chayama, Kazuyuki Hamaguchi, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Toshiie Sakata, Kiyoji Tanaka, Yuji Matsuzawa, Kazuwa Nakao, Akihiro Sekine

JOURNAL OF HUMAN GENETICS 56 ( 10 ) 716 - 719 2011.10

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

Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation. Journal of Human Genetics (2011) 56, 716-719; doi:10.1038/jhg.2011.86; published online 28 July 2011

DOI： 10.1038/jhg.2011.86

Two novel mutations of lecithin:cholesterol acyltransferase (LCAT) gene and the influence of APOE genotypes on clinical manifestations Reviewed

Katayama, A., Wada, J., Kataoka, H.U., Yamasaki, H., Teshigawara, S., Terami, T., Inoue, K., Kanzaki, M., Murakami, K., Nakatsuka, A., Sugiyama, H., Koide, N., Bujo, H., Makino, H.

NDT Plus 4 ( 5 ) 299 - 302 2011.10

Association of variations in the FTO, SCG3 and MTMR9 genes with metabolic syndrome in a Japanese population Reviewed

Kikuko Hotta, Takuya Kitamoto, Aya Kitamoto, Seiho Mizusawa, 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, Hiroaki Masuzaki, Takato Ueno, Kazuyuki Hamaguchi, Kiyoji Tanaka, Kentaro Yamada, Toshiaki Hanafusa, Shinichi Oikawa, Hironobu Yoshimatsu, Toshiie Sakata, Yuji Matsuzawa, Kazuwa Nakao, Akihiro Sekine

JOURNAL OF HUMAN GENETICS 56 ( 9 ) 647 - 651 2011.9

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

Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single-nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 x 10(-5)) and rs1421085 (P=7.4 x 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP x SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome. Journal of Human Genetics (2011) 56, 647-651; doi: 10.1038/jhg.2011.74; published online 28 July 2011

DOI： 10.1038/jhg.2011.74

Involvement of MAPKs in ICAM-1 Expression in Glomerular Endothelial Cells in Diabetic Nephropathy Reviewed

Naomi Watanabe, Kenichi Shikata, Yasushi Shikata, Kei Sarai, Kazuyoshi Omori, Ryo Kodera, Chikage Sato, Jun Wada, Hirofumi Makino

ACTA MEDICA OKAYAMA 65 ( 4 ) 247 - 257 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Inflammatory processes are involved in the pathogenesis of diabetic nephropathy. The aim of this study was to clarify the role of mitogen-activated protein kinase (MAPK) pathways for induction of intercellular adhesion molecule-1 (ICAM-1) expression in glomerular endothelial cells under diabetic conditions. We examined the expression of ICAM-1 in the kidneys of experimental diabetic rats. Human glomerular endothelial cells (GE cells) were exposed to normal glucose concentration, high glucose concentration (HG), or high mannitol concentration (HM), and then the expression of the ICAM-1 protein and the phosphorylation of the 3 subfamilies of mitogen-activated protein kinase (MAPK) were determined using Western blot analysis. Next, to evaluate the involvement of MAPKs in HG- or HM-induced ICAM-1 expression, we preincubated GE cells with the inhibitors for ERK, p38 or JNK 1h prior to the application of glucose or mannitol. Expression of ICAM-1 was increased in the glomeruli of diabetic rats. Both FIG and HM induced ICAM-1 expression and phosphorylation of ERK1/2, p38 and JINX in GE cells. Expression of ICAM-1 was significantly attenuated by inhibitors of ERK, p38 and JNK. We conclude that activation of ERK1/2, p38 and JNK cascades may be involved in ICAM-1 expression in glomerular endothelial cells under diabetic conditions.

DOI： 10.18926/AMO/46850

Icodextrin Increases Technique Survival Rate in Peritoneal Dialysis Patients with Diabetic Nephropathy by Improving Body Fluid Management: A Randomized Controlled Trial Reviewed

Yuji Takatori, Shigeru Akagi, Hitoshi Sugiyama, Junko Inoue, Shoichiro Kojo, Hiroshi Morinaga, Kazushi Nakao, Jun Wada, Hirofumi Makino

CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 6 ( 6 ) 1337 - 1344 2011.6

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

Background and objectives There are still controversies whether peritoneal dialysis (PD) with icodextrin preserves residual renal and peritoneal membrane functions in patients with diabetes. However, there are no randomized controlled and long-term clinical trials in newly started PD patients with diabetic nephropathy.
Design, setting, participants, & measurements Forty-one patients with diabetic nephropathy with ESRD were enrolled and randomly assigned to the glucose group (GLU) treated with 8 L of 1.5% or 2.5% glucose or an icodextrin group (ICO) treated with 1.5 or 2.0 L of 7.5% icodextrin-containing solutions. Technique failure, body fluid management, glucose and lipid metabolism, and residual renal and peritoneal functions and were evaluated over 2 years.
Results The technique survival rate was 71.4% in ICo and 45.0% in GLU, with most of the technique failure due to volume overload. ICO showed significantly better cumulative technique survival. Net ultrafiltration volume was significantly higher in ICO throughout the study period. There were no beneficial effects of icodextrin on hemoglobin A1c, glycoalbumin, and lipid profile at 24 months. Urine volume and residual renal function declined faster in ICO, but there were no significant differences between the two groups. For peritoneal function, no differences were observed in dialysis-to-plasma creatinine ratios during the observation.
Conclusions In PD therapy for diabetic nephropathy, the use of icodextrin-containing solutions has a beneficial effect on technique survival, but there are no apparent benefits or disadvantages in residual renal and peritoneal functions compared with conventional PD with glucose solution. Clin J An, Soc Nephrol 6: 1337-1344, 2011. doi: 10.2215/CJN.10041110

DOI： 10.2215/CJN.10041110

Emphysematous Cystitis in a Patient with Type 2 Diabetes Mellitus Reviewed

Noriko Toyota, Daisuke Ogawa, Keita Ishii, Kyoji Hirata, Jun Wada, Kenichi Shikata, Hirofumi Makino

ACTA MEDICA OKAYAMA 65 ( 2 ) 129 - 133 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

A 62-year-old woman with a history of poorly controlled type 2 diabetes mellitus was admitted to our hospital with a 3-week history of mild fever, vomiting, and anorexia. Abdominal computed tomography (CT) showed bilateral hydronephrosis and gas accumulation in the urinary bladder wall and left ureter. Laboratory tests showed leukocytosis and elevated C-reactive protein level. Urine culture showed heavy growth of Escherichia coli. The final diagnosis was emphysematous cystitis. The patient was treated with systemic antibiotics and drainage using a urethral catheter. The clinical and radiographic findings resolved rapidly, and she was discharged from the hospital on day 28. Emphysematous cystitis is a relatively rare urinary tract infection associated with gas formation, and has the potential for a serious outcome if untreated. Early detection by imaging studies such as CT is important in providing prompt treatment and favorable clinical outcome.

Intercellular adhesion molecule-1 plays a critical role in glomerulosclerosis after subtotal nephrectomy Reviewed

Yuichi Kido, Daisuke Ogawa, Kenichi Shikata, Motofumi Sasaki, Ryo Nagase, Shinichi Okada, Hitomi Usui Kataoka, Jun Wada, Hirofumi Makino

CLINICAL AND EXPERIMENTAL NEPHROLOGY 15 ( 2 ) 212 - 219 2011.4

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

Hyperfiltration in the glomeruli have been considered to be an important cause of glomerular injury; however, the role of intercellular adhesion molecule (ICAM)-1 in the pathogenesis of glomerulosclerosis is not known.
To elucidate the effects of ICAM-1 depletion on hyperfiltration-induced glomerular disorder, we used subtotally nephrectomized ICAM-1(+/+) and ICAM-1(-/-) mice. We evaluated macrophage infiltration, mesangial matrix expansion, transforming growth factor (TGF)-beta and type IV collagen accumulation in glomeruli.
Macrophage infiltration into the glomeruli and mesangial matrix expansion coincident with increased expression of both ICAM-1 and TGF-beta, and accumulation of type IV collagen were ameliorated in subtotally nephrectomized ICAM-1(-/-) mice compared to ICAM-1(+/+) mice. ICAM-1 depletion significantly reduced hyperfiltration-induced glomerular injury after renal ablation.
Our present findings suggest that glomerular hyperfiltration is the leading cause of glomerulosclerosis, and it is mediated, at least in part, by ICAM-1 expression and macrophage infiltration.

DOI： 10.1007/s10157-010-0388-7

The Macrophage Is a Key Factor in Renal Injuries Caused by Glomerular Hyperfiltration Reviewed

Motofumi Sasaki, Kenichi Shikata, Shinichi Okada, Satoshi Miyamoto, Shingo Nishishita, Hitomi Usui Kataoka, Chikage Sato, Jun Wada, Daisuke Ogawa, Hirofumi Makino

ACTA MEDICA OKAYAMA 65 ( 2 ) 81 - 89 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Glomerular hyperfiltration is a common pathway leading to glomerulosclerosis in various kinds of kidney diseases. The 5/6 renal ablation is an established experimental animal model for glomerular hyperfiltration. On the other hand, low-grade inflammation is also a common mechanism for the progression of kidney diseases including diabetic nephropathy and atherosclerosis. Here we analyzed the gene expression profile in the remnant kidney tissues of 5/6 nephrectomized mice using a DNA microarmy system and compared it with that of sham-operated control mice. The 5/6 nephrectomized mice showed glomerular hypertrophy and an increase in the extracellular matrix in the glomeruli. DNA microarray analysis indicated the up-regulated expression of various kinds of genes related to the inflammatory process in remnant kidneys. We confirmed the up-regulated expression of platelet factor-4, and monocyte chemoattractant protein-1, 2, and 5 in remnant kidneys by RT-PCR. The current results; suggest that the inflammatory process is involved in the progression of glomerulosclerosis and is a common pathway of the pathogenesis of kidney disease.

Activation of Peroxisome Proliferator-Activated Receptor delta Inhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice Reviewed

Yuichi Matsushita, Daisuke Ogawa, Jun Wada, Noriko Yamamoto, Kenichi Shikata, Chikage Sato, Hiromi Tachibana, Noriko Toyota, Hirofumi Makino

DIABETES 60 ( 3 ) 960 - 968 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER DIABETES ASSOC

OBJECTIVE-Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-delta has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPAR delta is atheroprotective; however, the role of PPAR delta in renal function remains unclear. Here, we report the renoprotective effects of PPAR delta activation in a model of streptozotocin-induced diabetic nephropathy.
RESEARCH DESIGN AND METHODS-Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and,9) diabetic mice treated with the PPAR delta agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes.
RESULTS-GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPAR delta activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression.
CONCLUSIONS-These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPAR delta agonists and support the concept that PPAR delta agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy. Diabetes 60:960-968, 2011

DOI： 10.2337/db10-1361

P-Selectin Glycoprotein Ligand-1 Deficiency Is Protective Against Obesity-Related Insulin Resistance Reviewed

Chikage Sato, Kenichi Shikata, Daisho Hirota, Motofumi Sasaki, Shingo Nishishita, Satoshi Miyamoto, Ryo Kodera, Daisuke Ogawa, Atsuhito Tone, Hitomi Usui Kataoka, Jun Wada, Nobuo Kajitani, Hirofumi Makino

DIABETES 60 ( 1 ) 189 - 199 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER DIABETES ASSOC

OBJECTIVE An inflammatory process is involved in the mechanism of obesity-related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue.
RESEARCH DESIGN AND METHODS We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1(-/-)) mice compared with wild-type (WT) mice fed HFD.
RESULTS DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real-time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1-/- mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1-/- mice compared with WT mice fed HFD.
CONCLUSIONS These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance. Diabetes 60:189-199, 2011

DOI： 10.2337/db09-1894

High Glucose Increases Metallothionein Expression in Renal Proximal Tubular Epithelial Cells Reviewed

Daisuke Ogawa, Masato Asanuma, Ikuko Miyazaki, Hiromi Tachibana, Jun Wada, Norio Sogawa, Takeshi Sugaya, Shinji Kitamura, Yohei Maeshima, Kenichi Shikata, Hirofumi Makino

EXPERIMENTAL DIABETES RESEARCH 2011

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

Metallothionein(MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

DOI： 10.1155/2011/534872

Discovery of Genes Related to Diabetic Nephropathy in Various Animal Models by Current Techniques Reviewed

Jun Wada, Lin Sun, Yashpal S. Kanwar

EXPERIMENTAL MODELS FOR RENAL DISEASES: PATHOGENESIS AND DIAGNOSIS 169 161 - 174 2011

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

One of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy. The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD. With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with up-to-date innovative measures. In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies. Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome-wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) coupled with mass spectroscopic analysis. Several genes, such as Tim44 (translocase of inner mitochondrial membrane-44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenate), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase-3 beta isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents. Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy. Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histonemethylation profiling, metabolomic approaches (e.g. metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000313951

[Obesity: Progress in diagnosis and treatment; Topics, IV. Recent topics: 3. Obesity and new secretory factors; 1) Vaspin].

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

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 ( 4 ) 2011

Regulation of human serum vaspin levels and metabolic syndrome

Wada, J.

Therapeutic Research 32 ( 6 ) 2011

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