Faculty Profiles - WADA Jun

Papers - WADA Jun

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Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes Reviewed

Yu Wang, Akihiro Katayama, Takahiro Terami, Xiaoying Han, Tomokazu Nunoue, Dongxiao Zhang, Sanae Teshigawara, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Daisuke Ogawa, Yasuhide Furuta, Hirofumi Makino, Jun Wada

METABOLISM-CLINICAL AND EXPERIMENTAL 64 ( 6 ) 677 - 688 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Objective. In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70.
Methods. We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity.
Results. The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm11 and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opal, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow.
Conclusions. The Timm44 gene may be a new target for the treatment of type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2015.02.004

Risk factors for the development of glucocorticoid-induced diabetes mellitus Reviewed

Takayuki Katsuyama, Ken-Ei Sada, Sayaka Namba, Haruki Watanabe, Eri Katsuyama, Toshio Yamanari, Jun Wada, Hirofumi Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 108 ( 2 ) 273 - 279 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Aims: To evaluate the incidence of glucocorticoid-induced diabetes mellitus (GC-DM) by repeated measurements of the postprandial glucose and detect predictors for the development of GC-DM.
Methods: Inpatients with rheumatic or renal disease who received glucocorticoid therapy were enrolled in this study. We compared the clinical and laboratory parameters of the GC-DM group with the non-GC-DM group and performed a multivariate analysis to identify risk factors.
Results: During a four-week period, 84 of the 128 patients (65.6%) developed GC-DM. All patients were diagnosed based on the detection of postprandial hyperglycemia. The GC-DM group had an older age (65.2 vs. 50.4 years, p < 0.0001), higher levels of fasting plasma glucose (93.3 vs. 89.0 mg/dl, p = 0.027) and HbA1c (5.78 vs. 5.50%, 39.7 vs. 36.6 mmol/mol, p = 0.001) and lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m(2), p = 0.0003) than the non-GC-DM group. According to the multivariate analysis, an older age (more than or equal to 65 years), higher HbA1c level (more than or equal to 6.0%) and lower eGFR (<40 ml/min/1.73 m(2)) were identified as independent risk factors for GC-DM (OR 2.95, 95% CI 1.15-7.92, OR: 3.05, 95% CI 1.11-9.21, OR: 3.42, 95% CI: 1.22-10.8, respectively). The risk ratio for the development of GC-DM in the patients with at least one of these three risk factors was 2.28. The dose of glucocorticoids was not statistically related to the development of GC-DM.
Conclusions: Patients with an older age, higher HbA1c level and lower eGFR require close monitoring for the development of GC-DM, regardless of the dose of glucocorticoids being administered. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2015.02.010

Identification of Circulating miR-101, miR-375 and miR-802 as Biomarkers for Type 2 Diabetes Reviewed

Chigusa Higuchi, Atsuko Nakatsuka, Jun Eguchi, Sanae Teshigawara, Motoko Kanzaki, Akihiro Katayama, Satoshi Yamaguchi, Naoto Takahashi, Kazutoshi Murakami, Daisuke Ogawa, Sakiko Sasaki, Hirofumi Makino, Jun Wada

METABOLISM-CLINICAL AND EXPERIMENTAL 64 ( 4 ) 489 - 497 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Purpose. The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice.
Basic Procedures. We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT).
Main Findings. The serum concentrations of miRNAs, log10miR-101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41 +/- 2.01 u.s. -0.57 +/- 1.05 (P = 1.36 x 10(-5)), 0.20 +/- 0.58 v.s. 0.038 +/- 1.00 (P = 3.06 x 10(-6)), and 2.45 +/- 1.27 u.s. 0.97 +/- 0.98 (P = 0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08 +/- 1.35 v.s. 0.38 +/- 1.21 (P = 0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants.
Principal Conclusions. The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2014.12.003

AUTOIMMUNE PANCREATITIS AND MINIMAL CHANGE NEPHROTIC SYNDROME: AN UNUSUAL ASSOCIATION? Reviewed

Yuka Okuyama, Haruhito Adam Uchida, Masafumi Tenta, Tomokazu Nunoue, Ryoko Umebayashi, Hiroshi Morinaga, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Jun Wada

NEPHROLOGY 20 ( 3 ) 225 - 226 2015.3

Cognitive and affective functions in diabetic patients associated with diabetes-related factors, white matter abnormality and aging Reviewed

N. Hishikawa, T. Yamashita, K. Deguchi, J. Wada, K. Shikata, H. Makino, K. Abe

EUROPEAN JOURNAL OF NEUROLOGY 22 ( 2 ) 313 - 321 2015.2

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

Background and purposeDiabetes mellitus (DM) is associated with a decline in cognitive and affective functions.
MethodsIn all, 182 outpatients with DM were investigated for associations of cognitive and affective functions with diabetes-related factors and cerebral white matter abnormalities. In addition, the difference in cognitive decline of age-matched late elderly normal subjects and DM patients was investigated.
ResultsThe present study revealed that cognitive and affective functions declined in some DM patients. Furthermore, the decline in these functions was unrelated to fasting blood sugar level but was related to glycosylated hemoglobin (HbA1c) and insulin resistance. Poor HbA1c control was associated with a significant decline in the calculation' subscale and insulin resistance for naming', read list of letters' and delayed recall' Montreal Cognitive Assessment (MoCA) subscale scores. Magnetic resonance imaging scans showed that both periventricular hyperintensity (PVH) and deep white matter hyperintensity were associated with Mini Mental State Examination (MMSE) and MoCA scores, but only PVH was related to homeostasis model assessment of insulin resistance scores. Compared with age-matched late elderly normal subjects, orientation to time' and registration' MMSE subscales declined in late elderly DM patients.
ConclusionsThese results suggest that cognitive and affective decline in DM patients was mostly related to glucose control and insulin resistance, whilst amongst late elderly subjects the impairment of attention' and orientation' were characteristic features of DM patients.

DOI： 10.1111/ene.12568

Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator-activated receptor gamma (PPAR gamma)-selective antagonists based on the helix12-folding inhibition hypothesis Reviewed

Masao Ohashi, Kanae Gamo, Yuta Tanaka, Minoru Waki, Yoko Beniyama, Kenji Matsuno, Jun Wada, Masafumi Tenta, Jun Eguchi, Makoto Makishima, Nobuyasu Matsuura, Takuji Oyama, Hiroyuki Miyachi

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 90 53 - 67 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonists are candidates for treatment of type 2 diabetes, obesity and osteoporosis. However, few rational design strategies are currently available. Here, we utilized the helix12 (H12)-folding inhibition hypothesis, in combination with our previously determined X-ray crystal structure of PPAR gamma agonist MEKT-21 (6) complexed with the PPAR gamma ligand-binding domain, to design and develop a potent phenylalkynyl amide-type PPAR gamma antagonist 9i, focusing initially on pinpoint structural modification of the propanoic acid moiety of 6. Since 9i retained very weak, but distinct, PPAR gamma agonist activity, we next modified the distal benzene ring of 9i, aiming to delete the residual PPAR gamma agonist activity while retaining the antagonist activity. Introduction of a chlorine atom at the 2-position of the distal benzene ring afforded 9p, which exhibited potent, PPAR gamma-selective full antagonist activity without detectable agonist activity. We found that 9p stabilized the corepressor PPAR gamma complex and suppressed basal PPAR gamma activity. This compound showed anti-adipogenesis activity at the cellular level. This agonist antagonist switching concept based on the H12-folding inhibition hypothesis should also be applicable for designing other classes of PPAR gamma full antagonists. (C) 2014 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.ejmech.2014.11.017

ADIPOQ polymorphisms are associated with insulin resistance in Japanese women

Kitamoto, Aya, Kitamoto, Takuya, So, Rina, Matsuo, Tomoaki, Nakata, Yoshio, Hyogo, Hideyuki, Ochi, Hidenori, Nakamura, Takahiro, Kamohara, Seika, Miyatake, Nobuyuki, Kotani, Kazuaki, Mineo, Ikuo, Wada, Jun, Ogawa, Yuji, Yoneda, Masato, Nakajima, Atsushi, Funahashi, Tohru, Miyazaki, Shigeru, Tokunaga, Katsuto, Masuzaki, Hiroaki, Ueno, Takato, Chayama, Kazuaki, Hamaguchi, Kazayuki, Yamada, Kentaro, Hanafusa, Toshiaki, Oikawa, Shinichi, Sakata, Toshiie, Tanaka, Kiyoji, Matsuzawa, Yuji, Hotta, Kikuko

ENDOCRINE JOURNAL 62 ( 6 ) 513 - 521 2015

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

Visceral fat accumulation contributes to the development of insulin resistance, leading to metabolic syndrome. Adiponectin provides a link between visceral fat accumulation and insulin resistance. In addition to environmental factors, genetic factors play important roles in visceral fat accumulation and circulating adiponectin levels. Genome-wide association studies (GWASs) have identified genetic variations in the adiponectin, C1Q and collagen domain containing (ADIPOQ) gene that are associated with adiponectin levels. In this study, we investigated whether ADIPOQ single nucleotide polymorphisms (SNPs) were associated with visceral fat accumulation and insulin resistance. We measured the visceral fat area (VFA) by computed tomography (CT) and examined the presence of the insulin resistance-related phenotype (fasting plasma glucose, fasting insulin, and homeostasis model assessment-insulin resistance [HOMA-IR]) in a set of Japanese individuals (731 men and 864 women) who were genotyped for seven ADIPOQ SNPs reported by recent GWASs (namely, rs6810075, rs10937273, rs1648707, rs864265, rs182052, rs17366568, and rs6773957). SNPs associated with the phenotype (P < 0.05) were then evaluated by association analysis using a second set of the study participants (383 men and 510 women). None of the SNPs was associated with body mass index (BMI) or VFA in men or women. However, the adiponectin-decreasing alleles of rs10937273 and rs1648707 were significantly associated with HOMA-IR (P = 0.0030 and P = 0.00074, respectively) in women, independently of BMI. These SNPs were significantly associated with decreased adiponectin levels in women. Our results suggested that rs10937273 and rs1648707 may affect insulin sensitivity by regulating adiponectin production by adipose tissue in women.

DOI： 10.1507/endocrj.EJ14-0574

Factors Associated with Remission and/or Regression of Microalbuminuria in Type 2 Diabetes Mellitus Reviewed

Tetsuichiro Ono, Kenichi Shikata, Mikako Obika, Nobuyuki Miyatake, Ryo Kodera, Daisyo Hirota, Jun Wada, Hitomi Kataoka, Daisuke Ogawa, Hirofumi Makino

ACTA MEDICA OKAYAMA 68 ( 4 ) 235 - 241 2014.8

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

The aim of this study was to clarify the factors associated with the remission and/or regression of microalbuminuria in Japanese patients with type 2 diabetes mellitus. We retrospectively analyzed the data of 130 patients with type 2 diabetes mellitus with microalbuminuria for 2-6 years (3.39 +/- 1.31 years). Remission was defined as improving from microalbuminuria to normoalbuminuria using the albumin/creatinine ratio (ACR), and regression of microalbuminuria was defined as a decrease in ACR of 50% or more from baseline. Progression of microalbuminuria was defined as progressing from microalbuminuria to overt proteinuria during the follow-up period. Among 130 patients with type 2 diabetes mellitus with microalbuminuria, 57 and 13 patients were defined as having remission and regression, respectively, while 26 patients progressed to overt proteinuria. Sex (female), higher HDL cholesterol and lower HbAlc were determinant factors associated with remission/regression of microalbuminuria by logistic regression analysis. Lower systolic blood pressure (SBP) was also correlated with remission/regression, but not at a significant level. These results suggest that proper control of blood glucose, BP and lipid profiles may be associated with remission and/or regression of type 2 diabetes mellitus with microalbuminuria in clinical practice.

Long-Term Treatment with the Sodium Glucose Cotransporter 2 Inhibitor, Dapagliflozin, Ameliorates Glucose Homeostasis and Diabetic Nephropathy in db/db Mice Reviewed

Naoto Terami, Daisuke Ogawa, Hiromi Tachibana, Takashi Hatanaka, Jun Wada, Atsuko Nakatsuka, Jun Eguchi, Chikage Sato Horiguchi, Naoko Nishii, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

PLOS ONE 9 ( 6 ) e100777 2014.6

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

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic beta-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-beta, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, beta-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

DOI： 10.1371/journal.pone.0100777

Serum vaspin levels are associated with physical activity or physical fitness in Japanese: a pilot study

Nobuyuki Miyatake, Jun Wada, Atsuko Nakatsuka, Noriko Sakano, Sanae Teshigawara, Motohiko Miyachi, Izumi Tabata, Takeyuki Numata

ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE 19 ( 3 ) 200 - 206 2014.5

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

To investigate the link between serum vaspin levels and physical activity and/or physical fitness in Japanese.
A total of 156 subjects (81 men and 75 women) was enrolled in this cross-sectional study. Serum vaspin levels, physical activity by uniaxial accelerometers, peak oxygen uptake, and metabolic risk parameters were evaluated. We also assessed anthropometric and body composition parameters.
Serum vaspin levels were over the level of 10 ng/mL in 15 subjects (9.6 %: Vaspin High group). In Vaspin Low group (< 5 ng/mL: 74 men and 67 women), serum vaspin levels were 0.12 +/- A 0.18 ng/mL in men and 0.39 +/- A 0.70 ng/mL in women. Peak oxygen uptake was significantly and positively correlated with serum vaspin levels even after adjusting for age, physical activity evaluated by I [metabolic pound equivalents x h per week (METsa <...h/w)], BMI, and other confounding factors in men. In turn, physical activity was significantly and positively correlated with serum vaspin levels even after adjusting for confounding factors in women.
Serum vaspin levels were closely associated with physical fitness in men and physical activity in women independent of body composition in this Japanese cohort.

DOI： 10.1007/s12199-013-0375-1

Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy Reviewed

Mayu Watanabe, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Chigusa Higuchi, Akihiro Katayama, Sanae Teshigawara, Jun Eguchi, Daisuke Ogawa, Eijiro Watanabe, Jun Wada, Hirofumi Makino

PLOS ONE 9 ( 3 ) e92647 2014.3

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

Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt-/-mice, the glomerular hypertrophy and albuminuria in Pemt-/- mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt-/- diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.

DOI： 10.1371/journal.pone.0092647

Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats Reviewed

Toru Miyoshi, Kazufumi Nakamura, Masashi Yoshida, Daiji Miura, Hiroki Oe, Satoshi Akagi, Hiroki Sugiyama, Kaoru Akazawa, Tomoko Yonezawa, Jun Wada, Hiroshi Ito

CARDIOVASCULAR DIABETOLOGY 13 43 2014.2

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

Background: Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats.
Methods: Male Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days.
Results: Blood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 +/- 0.40, ISO: 4.43 +/- 0.39, ISO-VL: 4.14 +/- 0.29, vehicle-VL: 3.16 +/- 0.16, p < 0.05). Cardiac catheterization revealed that vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-alpha, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4.
Conclusions: Vildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats.

DOI： 10.1186/1475-2840-13-43

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice Reviewed

Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

American Journal of Physiology - Renal Physiology 306 ( 1 ) F105 - F115 2014.1

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

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney
however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy. © 2014 the American Physiological Society.

DOI： 10.1152/ajprenal.00034.2013

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice Reviewed

Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 306 ( 1 ) F105 - F115 2014.1

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

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

DOI： 10.1152/ajprenal.00034.2013

Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines Reviewed

Daisuke Ogawa, Jun Eguchi, Jun Wada, Naoto Terami, Takashi Hatanaka, Hiromi Tachibana, Atsuko Nakatsuka, Chikage Sato Horiguchi, Naoko Nishii, Hirofumi Makino

PLOS ONE 9 ( 1 ) e85594 2014.1

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

Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-gamma (PPAR gamma) and PPAR alpha, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4 alpha, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPAR delta was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor alpha in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.

DOI： 10.1371/journal.pone.0085594

Sarcoid-like lung granulomas in a hemodialysis patient treated with a dipeptidyl peptidase-4 inhibitor Reviewed

Ken-Ei Sada, Jun Wada, Hiroshi Morinaga, Shigeyuki Tuchimochi, Mayu Uka, Hirofumi Makino

Clinical Kidney Journal 7 ( 2 ) 182 - 185 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

It has been reported that the inhibition of dipeptidyl peptidase-4 (DPP-4)/CD26 on T-cells by DPP-4 enzymatic inhibitors suppresses lymphocyte proliferation and reduces the production of various cytokines, including tumor necrosis factor (TNF)-α. A 72-year-old female with diabetic nephropathy on hemodialysis developed multiple lung nodules following the administration of vildagliptin. A biopsy demonstrated the histology of granulomas without caseous necrosis. The discontinuation of vildagliptin resulted in the disappearance of the granulomas within 4 months. As granulomatosis often develops in patients under anti-TNF-α therapy, the accumulation of DPP-4 inhibitors or its metabolites is possibly linked to unrecognized complications, such as sarcoid-like lung granulomas. © 2014 © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

DOI： 10.1093/ckj/sft172

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

The chemiexcitation of the chemiluminescence of lophine peroxide anions via a partially cyclic transition state

Lu, G., Wada, J., Kimoto, T., Iga, H., Nishigawa, H., Kimura, M., Hu, Z.

European Journal of Organic Chemistry 2014 ( 6 ) 2014

Comparison of New Preservation Solutions, HN-1 and University of Wisconsin Solution, in Pancreas Preservation for Porcine Islet Isolation. Reviewed

Katayama A, Noguchi H, Kuise T, Nakatsuka A, Hirota D, Kataoka HU, Kawai T, Inoue K, Imagawa N, Saitoh I, Noguchi Y, Watanabe M, Wada J, Fujiwara T

Cell medicine 6 ( 1-2 ) 3 - 8 2013.12

Long-term effect of cinacalcet hydrochloride on abdominal aortic calcification in patients on hemodialysis with secondary hyperparathyroidism Reviewed

Kazunori Nakayama, Kazushi Nakao, Yuji Takatori, Junko Inoue, Shoichirou Kojo, Shigeru Akagi, Masaki Fukushima, Jun Wada, Hirofumi Makino

International Journal of Nephrology and Renovascular Disease 7 25 - 33 2013.12

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

Background: Secondary hyperparathyroidism (SHPT) is one of the common complications in dialysis patients, and is associated with increased risk of vascular calcification. The effects of cinacalcet hydrochloride treatment on bone and mineral metabolism have been previously reported, but the benefit of cinacalcet on vascular calcification remains uncertain. The aim of this study was to evaluate the impact of cinacalcet on abdominal aortic calcification in dialysis patients. Subjects and methods: Patients were on maintenance hemodialysis with insufficiently controlled SHPT (intact parathyroid hormone [PTH].180 pg/mL) by conventional therapies. All subjects were initially administered 25 mg cinacalcet daily, with concomitant use of calcitriol analogs. Abdominal aortic calcification was annually evaluated by calculating aortic calcification area index (ACAI) using multidetector computed tomography (MDCT), from 12 months before to 36 months after the initiation of cinacalcet therapy. Results: Twenty-three patients were analyzed in this study. The mean age was 59.0±8.7 years, 34.8% were women, and the mean dialysis duration was 163.0±76.0 months. After administration of cinacalcet, serum levels of intact PTH, phosphorus, and calcium significantly decreased, and mean Ca × P values significantly decreased from 67.4±7.9 mg2/dL2 to 52±7.7 mg2/dL2. Although the ACAI value did not decrease during the observation period, the increase in ACAI between 24 months and 36 months after cinacalcet administration was significantly suppressed. Conclusion: Long-term administration of cinacalcet was associated with reduced progression of abdominal aortic calcification, and achieving appropriate calcium and phosphorus levels may reduce the rates of cardiovascular events and mortality in patients on hemodialysis. © 2014 Nakayama et al.

DOI： 10.2147/IJNRD.S54731

Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes Reviewed

Takahiro Terami, Jun Wada, Kentaro Inoue, Atsuko Nakatsuka, Daisuke Ogawa, Sanae Teshigawara, Kazutoshi Murakami, Akihiro Katayama, Jun Eguchi, Hirofumi Makino

International Journal of Nephrology and Renovascular Disease 6 233 - 240 2013.10

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

Purpose: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin-angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and α1-microglobulin. Materials and methods: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and α1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51
RAS inhibitors [-], n=34). Results: Urinary angiotensinogen levels positively correlated with ACR (r =0.367, P=3.84×10-4) and urinary α1-microglobulin (r=0.734, P=1.32 × 10-15), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r=-0.350, P=1.02 × 10-3) and high-density lipoprotein cholesterol (r=-0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary α1-microglobulin as independent variables
only urinary α1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary α1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group. Conclusion: Urinary angiotensinogen is well correlated with urinary α1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes. © 2013 Terami et al.

DOI： 10.2147/IJNRD.S51829

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