Faculty Profiles - WADA Jun

Papers - WADA Jun

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Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin Microarray Reviewed

Kentaro Inoue, Jun Wada, Jun Eguchi, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Daisuke Ogawa, Takahiro Terami, Akihiro Katayama, Atsuhito Tone, Izumi Iseda, Kazuyuki Hida, Masao Yamada, Tomohisa Ogawa, Hirofumi Makino

PLoS ONE 8 ( 10 ) e77118 2013.10

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

We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Siaα2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40±0.43
A2, 0.60±0.53
A3 1.57±1.13 ng/gCr
p = 7.29×10-8) and of GFR stages (G1, 0.39±0.39
G2, 0.49±0.45
G3, 1.25±1.18
G4, 1.34±0.80 ng/gCr
p = 3.89×10-4). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR&lt
60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy. © 2013 Inoue et al.

DOI： 10.1371/journal.pone.0077118

NUDT3 rs206936 is associated with body mass index in obese Japanese women Reviewed

Kitamoto, A., Kitamoto, T., Mizusawa, S., Teranishi, H., So, R., Matsuo, T., Nakata, Y., Hyogo, H., Ochi, H., Nakamura, T., Kamohara, S., Miyatake, N., Kotani, K., Komatsu, R., Itoh, N., Mineo, I., Wada, J., Yoneda, M., Nakajima, A., Funahashi, T., Miyazaki, S., Tokunaga, K., Masuzaki, H., Ueno, T., Chayama, K., Hamaguchi, K., Yamada, K., Hanafusa, T., Oikawa, S., Sakata, T., Tanaka, K., Matsuzawa, Y., Nakao, K., Sekine, A., Hotta, K.

Endocrine Journal 60 ( 8 ) 991 - 1000 2013.8

Cell Cycle Abnormality in Metabolic Syndrome and Nuclear Receptors as an Emerging Therapeutic Target Reviewed

Atsuko Nakatsuka, Jun Wada, Hirofumi Makino

ACTA MEDICA OKAYAMA 67 ( 3 ) 129 - 134 2013.6

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future.

DOI： 10.18926/AMO/50405

Visceral Adipose Tissue-derived Serine Proteinase Inhibitor Inhibits Apoptosis of Endothelial Cells as a Ligand for the Cell-Surface GRP78/Voltage-dependent Anion Channel Complex Reviewed

Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

CIRCULATION RESEARCH 112 ( 5 ) 771 - + 2013.3

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

Rationale: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats.
Objective: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu.
Methods and Results: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using 125I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565x10(-9) m) by the treatment of 5 mu M thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca2+ influx and subsequent apoptosis.
Conclusions: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus. (Circ Res. 2013;112:771-780.)

DOI： 10.1161/CIRCRESAHA.111.300049

Current status of the treatment of microscopic polyangiitis and granulomatosis with polyangiitis in Japan Reviewed

Koichi Sugiyama, Ken-Ei Sada, Michiko Kurosawa, Jun Wada, Hirofumi Makino

Clinical and Experimental Nephrology 17 ( 1 ) 51 - 58 2013.2

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

Background: This study aimed to describe the epidemiologic characteristics of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan. Methods: We used the database of the Ministry of Health, Labour and Welfare (MHLW) from 2006 to 2008, and analyzed data from 938 patients (MPA = 697, GPA = 241) who fulfilled the MHLW diagnostic criteria and had registered within a year after onset. Results: The mean ages of the MPA and GPA patients were 69.4 ± 0.4 and 58.4 ± 1.1 years, respectively. Renal (86.9 %), chest (73.7 %), and nervous system (45.2 %) symptoms were common in MPA patients. Ear, nose, and throat (86.7 %), chest (78.0 %), and renal (60.6 %) symptoms were frequently observed in GPA patients. The concomitant use of cyclophosphamide (CY) with corticosteroids was observed in 22.2 % of the MPA patients and 58.5 % of the GPA patients. In multivariate analysis, the concomitant use of CY was associated with a younger age and pulmonary hemorrhage in MPA patients, and the avoidance of CY was associated with nervous system symptoms and rapidly progressive glomerulonephritis in GPA patients. Plasma exchanges were inducted in 5.2 % of the MPA patients and 4.1 % of the GPA patients. The addition of plasma exchange was associated with elevation of the serum creatinine level in patients with both MPA and GPA. Conclusion: A dominance of MPA and a reduced frequency of renal involvement in GPA patients may be significant features of the Japanese population. Clinical practice relating to MPA and GPA in Japan can be characterized as follows: CY is used less commonly, and plasma exchange is employed for patients with deteriorated renal function. © 2012 The Author(s).

DOI： 10.1007/s10157-012-0651-1

Inflammation and the pathogenesis of diabetic nephropathy Reviewed

Jun Wada, Hirofumi Makino

CLINICAL SCIENCE 124 ( 3-4 ) 139 - 152 2013.2

Language：English Publisher：PORTLAND PRESS LTD

The most problematic issue in clinical nephrology is the relentless and progressive increase in patients with ESRD (end-stage renal disease) worldwide. The impact of diabetic nephropathy on the increasing population with CKD (chronic kidney disease) and ESRD is enormous. Three major pathways showing abnormality of intracellular metabolism have been identified in the development of diabetic nephropathy: (i) the activation of polyol and PKC (protein kinase C) pathways; (ii) the formation of advanced glycation end-products; and (iii) intraglomerular hypertension induced by glomerular hyperfiltration. Upstream of these three major pathways, hyperglycaemia is the major driving force of the progression to ESRD from diabetic nephropathy. Downstream of the three pathways, microinflammation and subsequent extracellular matrix expansion are common pathways for the progression of diabetic nephropathy. In recent years, many researchers have been convinced that the inflammation pathways play central roles in the progression of diabetic nephropathy, and the identification of new inflammatory molecules may link to the development of new therapeutic strategies. Various molecules related to the inflammation pathways in diabetic nephropathy include transcription factors, pro-inflammatory cytokines, chemokines, adhesion molecules, Toll-like receptors, adipokines and nuclear receptors, which are candidates for the new molecular targets for the treatment of diabetic nephropathy. Understanding of these molecular pathways of inflammation would translate into the development of anti-inflammation therapeutic strategies.

DOI： 10.1042/CS20120198

The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO) Reviewed

Kazutoshi Murakami, Jun Wada, Daisuke Ogawa, Chikage Sato Horiguchi, Tomoko Miyoshi, Motofumi Sasaki, Haruhito A. Uchida, Yoshio Nakamura, Hirofumi Makino

DIABETES & VASCULAR DISEASE RESEARCH 10 ( 1 ) 93 - 96 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS LTD

Telmisartan partially activates the peroxisome proliferator-activated receptor gamma (PPAR gamma), which may ameliorate the accumulation of visceral adipose tissues and sensitise insulin action. Nineteen patients with essential hypertension and metabolic syndrome were randomly assigned to receive 40 mg of telmisartan (TELMI group) once daily or 80 mg of valsartan (VAL group) once daily for 24 weeks. The visceral fat area (VFA) measured by computed tomography (CT) was significantly reduced from 150.4 +/- 15.5 to 127.7 +/- 16.7 cm(2) in the TELMI group (p=0.049). Although VFA was also reduced in the VAL group from 169.8 +/- 14.8 to 155.3 +/- 14.8 cm(2), the change was not significant (p=0.173). There were no significant changes in body weight, body mass index (BMI), waist circumference, subdermal fat area (SFA), fasting plasma glucose, and homeostasis model assessment of insulin resistance (HOMA-IR) in comparison to the baseline and follow-up data in both groups. In conclusion, telmisartan may have a benefit in the reduction of visceral adipose tissues in comparison to valsartan.

DOI： 10.1177/1479164112444640

Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease Reviewed

Yuko Kurose, Jun Wada, Motoko Kanzaki, Sanae Teshigawara, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Mayu Watanabe, Chigusa Higuchi, Jun Eguchi, Nobuyuki Miyatake, Hirofumi Makino

BMC NEPHROLOGY 14 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (T(H)1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1).
Methods: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n = 182).
Results: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 +/- 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r = 0.227, p = 0.002), creatinine (r = 0.175, p = 0.018), urea nitrogen (r = 0.162, p = 0.028) and osmotic pressure (r = 0.187, p = 0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.188, p = 0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p = 0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3.
Conclusion: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.

DOI： 10.1186/1471-2369-14-23

Replication Study of 15 Recently Published Loci for Body Fat Distribution in the Japanese Population Reviewed

Kikuko Hotta, Aya Kitamoto, Takuya Kitamoto, Seiho Mizusawa, Hajime Teranishi, Rina So, Tomoaki Matsuo, Yoshio Nakata, Hideyuki Hyogo, Hidenori Ochi, Takahiro Nakamura, Seika Kamohara, Nobuyuki Miyatake, Kazuaki Kotani, 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, Toshiie Sakata, Kiyoji Tanaka, Yuji Matsuzawa, Kazuwa Nakao, Akihiro Sekine

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 20 ( 4 ) 336 - 350 2013

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

Aim: Visceral fat accumulation plays an integral role in morbidity and mortality rates by increasing the risk of developing metabolic disorders such as type 2 diabetes, dyslipidemia, and hypertension. New genetic loci associated with fat distribution, measured by waist-hip ratios and computed tomography (CT), have recently been identified by genome-wide association studies in European-descent populations. This study used CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to fat distribution are associated with visceral fat area (VFA) and subcutaneous fat area (SFA) in the Japanese population.
Methods: We measured the VFAs and SFAs of 1424 obese Japanese subjects (BMI >= 25 kg/m(2), 635 men and 789 women) that were genotyped at 15 SNPs, namely, TBX15 rs984222, DNM3 rs1011731, LYPLAL1 rs4846567, GRB14 rs10195252, NISCH rs6784615, ADAMTS9 rs6795735, CPEB4 rs6861681, LY86 rs1294421, VEGFA rs6905288, RSPO3 rs9491696, NFE2L3 rs1055144, ITPR2 rs718314, HOXC13 rs1443512, ZNRF3 rs4823006 and THNSL2 rs1659258.
Results: The G-allele of LYPLAL1 rs4846567 was borderline associated with an increased ratio of VFA to SFA (V/S ratio; p=0.0020). LYPLAL1 rs4846567 had a stronger effect on the V/S ratio in women (p=0.0078) than in men (p=0.12); however, neither result was significant after Bonferroni correction for multiple comparisons. NISCH rs6784615 was nominally associated with increased VFA (p=0.040) and V/S ratio (p=0.020). The other SNPs analyzed were not significantly associated with body mass index (BMI), VFA, or SFA.
Conclusion: Our results suggest that LYPLAL1 rs4846567 and NISCH rs6784615 may influence fat distribution in the Japanese population.

DOI： 10.5551/jat.14589

Other Link： http://orcid.org/0000-0003-1468-5170

The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO) (vol 10, pg 93, 2013)

Jun Wada

Diabetes and Vascular Disease Research 10 ( 6 ) 554 - 554 2013

Erratum: Telmisartan attenutes diabetic nephropathy by suppressing oxisative stress in db/db mice (Nephron - Experimental Nephrology (2012) 121 (e97-e108) DOI: 10.1159/00343102)

Sato-Horiguchi, C., Ogawa, D., Wada, J., Tachibana, H., Kodera, R., Eguchi, J., Nakatsuka, A., Terami, N., Shikata, K., Makino, H.

Nephron - Experimental Nephrology 123 ( 3-4 ) 46 - 46 2013

Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines

Jun Wada

Diabetes 2013

The serum vaspin levels are reduced in Japanese chronic hemodialysis patients Reviewed

Junko Inoue, Jun Wada, Sanae Teshigawara, Kazuyuki Hida, Atsuko Nakatsuka, Yuji Takatori, Shoichirou Kojo, Shigeru Akagi, Kazushi Nakao, Nobuyuki Miyatake, John F. McDonald, Hirofumi Makino

BMC NEPHROLOGY 13 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.
Methods: Healthy Japanese control volunteers (control; n = 95, 49.9 +/- 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 +/- 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.
Results: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; Vaspin(High) group), while the rest of the population exhibited lower levels (< 3 ng/ml; Vaspin(Low) group). By comparing the patients in the Vaspin(Low) group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 +/- 0.24 ng/ml) than in the HD patients (0.32 +/- 0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.
Conclusions: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin(Low) group.

DOI： 10.1186/1471-2369-13-163

Case of emphysematous cholecystitis in a patient with type 2 diabetes mellitus associated with schizophrenia Reviewed

Ayu Ogawa, Kenichi Shikata, Haruhito Adam Uchida, Susumu Shinoura, Naosuke Yokomichi, Daisuke Ogawa, Chicage Sato-Horiguchi, Takahito Yagi, Jun Wada, Hirofumi Makino

JOURNAL OF DIABETES INVESTIGATION 3 ( 6 ) 534 - 535 2012.12

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

Emphysematous cholecystitis is a rare, but life-threatening, form of acute cholecystitis caused by gas-forming organisms in the gallbladder. A 73-year-old male patient with type 2 diabetes mellitus complicated with neuropathy associated with schizophrenia was admitted to Okayama University Hospital, Okayama, Japan, because of a high fever and general malaise. On the fourth hospital day, despite normal liver function tests and little abdominal pain, his abdominal computed tomography showed huge gas formation in the gallbladder lumen along with a dilated gallbladder with a thickened wall, consistent with emphysematous cholecystitis. The patient underwent an emergency open cholecystectomy. Few abdominal symptoms appeared because of the hyposensitivity to pain caused by not only diabetic neuropathy, but also antipsychotic agents the patient was taking for schizophrenia. Emphysematous cholecystitis should be taken into consideration for the differential diagnosis of high fever in diabetic patients with schizophrenia, irrespective of the level of liver function tests and clinical symptoms. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00232. x, 2012)

DOI： 10.1111/j.2040-1124.2012.00232.x

Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex Reviewed

Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

DIABETES 61 ( 11 ) 2823 - 2832 2012.11

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

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012

DOI： 10.2337/db12-0232

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy Reviewed

Hiromi Tachibana, Daisuke Ogawa, Yuichi Matsushita, Dennis Bruemmer, Jun Wada, Sanae Teshigawara, Jun Eguchi, Chikage Sato-Horiguchi, Haruhito Adam Uchida, Kenichi Shikata, Hirofumi Makino

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 23 ( 11 ) 1835 - 1846 2012.11

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

Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

DOI： 10.1681/ASN.2012010022

Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice Reviewed

Daisuke Kawai, Akinobu Takaki, Atsuko Nakatsuka, Jun Wada, Naofumi Tamaki, Tetsuya Yasunaka, Kazuko Koike, Ryuichiro Tsuzaki, Kazuyuki Matsumoto, Yasuhiro Miyake, Hidenori Shiraha, Manabu Morita, Hirofumi Makino, Kazuhide Yamamoto

HEPATOLOGY 56 ( 3 ) 912 - 921 2012.9

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

Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-cholinedeficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesisrelated genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912921)

DOI： 10.1002/hep.25782

Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population Reviewed

Sanae Teshigawara, Jun Wada, Kazuyuki Hida, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Izumi Iseda, Yuichi Matsushita, Nobuyuki Miyatake, John F. McDonald, Kikuko Hotta, Hirofumi Makino

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 97 ( 7 ) E1202 - E1207 2012.7

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

Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats.
Objective: We investigated genetic and nongenetic factors that define serum concentrations of vaspin.
Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138).
Results: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950.
Conclusions: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)

DOI： 10.1210/jc.2011-3297

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography Reviewed

Kikuko Hotta, Aya Kitamoto, Takuya Kitamoto, Seiho Mizusawa, Hajime Teranishi, Rina So, 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 ( 5 ) 305 - 310 2012.5

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

Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power. Journal of Human Genetics (2012) 57, 305-310; doi:10.1038/jhg.2012.21; published online 1 March 2012

DOI： 10.1038/jhg.2012.21

RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes Reviewed

Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Aya Hida, Jun Eguchi, Sanae Teshigawara, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Daisuke Ogawa, Hiroyuki Kagechika, Hirofumi Makino

JOURNAL OF PATHOLOGY 226 ( 5 ) 784 - 795 2012.4

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

The peroxisome proliferator activated receptor-gamma (PPAR gamma) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G(0)/G(1) cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G(0) + G(1) ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G(0)/G(1) cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G(0)/G(1) cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.3001

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