Faculty Profiles - WADA Jun

Papers - WADA Jun

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Hemophagocytic syndrome associated with fatal veno-occlusive disease in the liver Reviewed

Atsuko Nakatsuka, Jun Wada, Ryo Nagase, Masaya Takeda, Tadashi Yoshino, Hirofumi Makino

INTERNAL MEDICINE 46 ( 8 ) 495 - 499 2007

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

A 47-year-old man presented with hemophagocytic syndrome (HPS) without any obvious underlying diseases. On computed tomography, his liver was occupied by multiple ill-defined low intensity lesions. Liver biopsy revealed diffuse infiltration of numerous histiocytes without cytologic atypism and prominent fibrotic changes. These histiocyes showed S100(+), CD68(+), CD1a(-), and lysozyme(+) and Langerhans cell granules were not observed by electron microscopic examination. He failed to respond to immunosuppressive and chemotherapeutic treatments and progressed to severe liver failure. At autopsy, his liver exhibited veno-occulusive disease (VOD). Since VOD is regarded as a rare complication of HPS, the presence of VOD associated with HPS may be easily overlooked.

DOI： 10.2169/internalmedicine.46.6294

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Severe hypoglycemia induced by IGF-II producing non-islet cell tumor

Kanzaki, M., Kashihara, H., Kiura, K., Murakami, K., Iwagaki, H., Wada, J., Makino, H.

Internal Medicine 46 ( 13 ) 1061 - 1061 2007

Hypolipidemia of renal diseases

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

Nippon rinsho. Japanese journal of clinical medicine 65 Suppl 7 2007

Erratum: Macrophage scavenger receptor-A - Deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation (Diabetes (2007) 56, (263-372))

Usui, H.K., Shikata, K., Sasaki, M., Okada, S., Matsuda, M., Shikata, Y., Ogawa, D., Kido, Y., Nagase, R., Yozai, K., Ohga, S., Tone, A., Wada, J., Takeya, M., Horiuchi, S., Kodama, T., Makino, H.

Diabetes 56 ( 3 ) 897 - 897 2007

Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms Reviewed

T Okada, J Wada, K Hida, J Eguchi, Hashimoto, I, M Baba, A Yasuhara, K Shikata, H Makino

DIABETES 55 ( 6 ) 1666 - 1677 2006.6

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

Thiazolidinediones are ligands for peroxisome proliferator-activated receptor-activated receptor (PPAR)-gamma, widely used as insulin sensitizer in type 2 diabetic patients and implicated in apoptosis, cell proliferation, and cell cycle regulation. Here, the effect of thiazolidinediones on G1-phase cell cycle arrest, the hallmark in diabetic nephropathy, was investigated. Eight-week-old male Otsuka Long-Evans Tokushima fatty rats were treated with pioglitazone (1 mg kg body wt(-1) (.) day(-1)) until 50 weeks of age and compared with insulin treatment. Although similar HbA(1c) levels were observed in both groups, pioglitazone significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion compared with the insulin-treated group. In addition, pioglitazone significantly reduced the number of glomerular p27(Kip1)-positive cells. Because prominent expression of PPAR-gamma was observed in podocytes in glomeruli and cultured cells, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mmol/l D-glucose supplemented with pioglitazone. Pioglitazone inhibited cell hypertrophy revealed by [H-3]thymidine and [H-3]proline incorporation, and pioglitazone reversed high glucose-induced G1-phase cell cycle arrest, i.e., an increase in G0/G1 phase and decrease in S and G2 phases. Pioglitazone suppressed high glucose-induced phosphorylation of p44/42 mitogen-activated protein kinase and reduced Bcl-2 and P27(Kip1) protein levels. Besides glucose-lowering action, pioglitazone ameliorates diabetic nephropathy via cell cycle-dependent mechanisms.

DOI： 10.2337/db05-1285

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Elevated serum monocyte chemoattractant protein-4 and chronic inflammation in overweight subjects Reviewed

Izumi Hashimoto, Jun Wada, Aya Hida, Masako Baba, Nobuyuki Miyatake, Jun Eguchi, Kenichi Shikata, Hirofumi Makino

OBESITY 14 ( 5 ) 799 - 811 2006.5

Language：English Publishing type：Research paper (scientific journal) Publisher：NORTH AMER ASSOC STUDY OBESITY

Objective: Chronic inflammation observed in obesity has been reported to be implicated in the development of atherosclerosis. We screened candidate chemokines that link chronic inflammation and obesity.
Research Methods and Procedures: Japanese overweight (n = 39, BMI 28.7 +/- 0.65 kg/m(2)) and normal-weight (n = 24, BMI 22.3 +/- 0.45 kg/m(2)) subjects were enrolled. Using antibody-based protein microarray, spot intensities of monocyte chemoattractant protein (MCP)-4, eotaxin, and eotaxin-2 correlated with anthropometric parameters. We further measured serum concentration of these chemokines and mRNA levels in adipose tissues obtained from volunteers.
Results: Serum MCP-4 levels showed positive correlation with BMI (r = 0.318, p = 0.014), waist (r = 0.316, p = 0.018), and waist-to-hip ratio (WHR) (r = 0.264, p = 0.049). Furthermore, MCP-4 correlated with homeostasis model assessment of insulin resistance (r = 0.392, p = 0.002), high-sensitivity C-reactive protein (hsCRP) (r = 0.350, p = 0.006). In step-wise multiple regression analyses, hsCRP independently correlated with MCP-4 levels. The expression of MCP-4 mRNA in visceral adipose tissue positively correlates with BMI. Serum eotaxin levels correlate with BMI (r = 0.262, p = 0.045) and WHR (r = 0.383, p = 0.003). Serum eotaxin-2 levels correlated with BMI (r = 0.464, p < 0.001), waist (r = 0.333, p = 0.017), and WHR (r = 0.278, p = 0.048). However, eotaxin and eotaxin-2 levels did not show significant correlation with hsCRP.
Discussion: Serum levels of MCP-4, eotaxin, and eotaxin-2, which belong to CC chemokine family and share CC chemokine receptor 3, correlated with BMI. These chemokines, especially MCP-4, may be critical molecules that link obesity and chronic inflammation.

DOI： 10.1038/oby.2006.93

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Elevated serum monocyte chemoattractant protein-4 and chronic inflammation in overweight subjects Reviewed

Izumi Hashimoto, Jun Wada, Aya Hida, Masako Baba, Nobuyuki Miyatake, Jun Eguchi, Kenichi Shikata, Hirofumi Makino

Obesity 14 ( 5 ) 799 - 811 2006.5

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

Objective: Chronic inflammation observed in obesity has been reported to be implicated in the development of atherosclerosis. We screened candidate chemokines that link chronic inflammation and obesity. Research Methods and Procedures: Japanese overweight (n = 39, BMI 28.7 ± 0.65 kg/m 2) and normal-weight (n = 24, BMI 22.3 ± 0.45 kg/m 2) subjects were enrolled. Using antibody-based protein microarray, spot intensities of monocyte chemoattractant protein (MCP)-4, eotaxin, and eotaxin-2 correlated with anthropometric parameters. We further measured serum concentration of these chemokines and mRNA levels in adipose tissues obtained from volunteers. Results: Serum MCP-4 levels showed positive correlation with BMI (r = 0.318, p = 0.014), waist (r = 0.316, p = 0.018), and waist-to-hip ratio (WHR) (r = 0.264, p = 0.049). Furthermore, MCP-4 correlated with homeostasis model assessment of insulin resistance (r -0.392, p = 0.002), high-sensitivity C-reactive protein (hsCRP) (r = 0.350, p = 0.006). In step-wise multiple regression analyses, hsCRP independently correlated with MCP-4 levels. The expression of MCP-4 mRNA in visceral adipose tissue positively correlates with BMI. Serum eotaxin levels correlate with BMI (r = 0.262, p = 0.045) and WHR (r = 0.383, p = 0.003). Serum eotaxin-2 levels correlated with BMI (r = 0.464, p &lt
0.001), waist (r = 0.333, p = 0.017), and WHR (r = 0.278, p = 0.048). However, eotaxin and eotaxin-2 levels did not show significant correlation with hsCRP. Discussion: Serum levels of MCP-4, eotaxin, and eotaxin-2, which belong to CC chemokine family and share CC chemokine receptor 3, correlated with BMI. These chemokines, especially MCP-4, may be critical molecules that link obesity and chronic inflammation. Copyright © 2006 NAASO.

DOI： 10.1038/oby.2006.93

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Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production Reviewed

Yanling Zhang, Jun Wada, Izumi Hashimoto, Jun Eguchi, Akihiro Yasuhara, Yashpal S. Kanwar, Kenichi Shikata, Hirofumi Makino

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 17 ( 4 ) 1090 - 1101 2006.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMERICAN SOCIETY NEPHROLOGY

Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species has emerged as a major player in diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane 44 (TIM44) was identified by upregulation in diabetic mouse kidneys. TIM44 functions as a membrane anchor of mitochondrial heat-shock protein 70 (mtHsp70) to TIM23 complex and is involved in the import of mitochondria-targeted preproteins into mitochondrial matrix. The process is dependent on inner membrane potential and ATP hydrolysis on ATPase domain of mitochondrial heat-shock protein 70. Hemagglutination virus of Japan-envelope vector that carries pcDNA3.1 plasmid that contains the full-length cDNA of TIM44 and control plasmid were injected weekly into the tail vein of uninephrectomized streptozotocin-induced diabetic CD-1 mice. The gene delivery alleviated proteinuria and renal hypertrophy at 8 wk after the injection, inhibited renal cell proliferation and apoptosis, and suppressed superoxide production. In vitro experiments, using human proximal tubular (HK2) cells, revealed that the gene delivery of TIM44 reversed high glucose-induced metabolic and cellular abnormalities such as enhanced reactive oxygen species production, increased ATP contents, alterations in inner membrane potential, increased cell proliferation, and apoptosis. Transfection with siRNA and expressing vector of TIM44 revealed that TIM44 facilitates import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase into mitochondria. The gene delivery of TIM44 therefore seems to be beneficial for the maintenance of mitochondrial function and is a novel therapeutic approach for diabetic nephropathy.

DOI： 10.1681/ASN.2005111148

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The application of synthetic hANP in diabetic nephropathy with nephrotic syndrome Reviewed

Y Kikumoto, J Wada, H Makino

DIABETES CARE 29 ( 1 ) 172 - 173 2006.1

Relationship between metabolic syndrome and cigarette smoking in the Japanese population Reviewed

Nobuyuki Miyatake, Jun Wada, Yuriko Kawasaki, Kenji Nishii, Hirofumi Makino, Takeyuki Numata

INTERNAL MEDICINE 45 ( 18 ) 1039 - 1043 2006

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

Objective We investigated the link between metabolic syndrome and cigarette smoking in the Japanese population.
Methods A total of 3,177 Japanese subjects aged 20-79 years were recruited in a cross-sectional clinical investigation study. Habits of cigarette smoking were obtained at interviews by well-trained staff. The diagnosis of metabolic syndrome was based on the new criterion in Japan.
Results Four hundred and forty men (35.3%) and 142 women (7.4%) were current smokers. Three hundred thirty four men (26.8%) and 69 women (3.6%) were diagnosed as metabolic syndrome. The prevalence of current smoker in subjects with metabolic syndrome was significantly higher than in subjects with non-metabolic syndrome in men with and without adjustment for age. The prevalence of metabolic syndrome in men with Brinkman index >= 600 was significantly higher than that in men with Brinkman index<600.
Conclusion The present study indicated that cigarette smoking may be an important modifiable factor in Japanese men with metabolic syndrome.

DOI： 10.2169/internalmedicine.45.1850

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Relationship between metabolic syndrome and proteinuria in the Japanese population Reviewed

Nobuyuki Miyatake, Jun Wada, Yuriko Kawasaki, Sumiko Matsumoto, Hirofumi Makino, Takeyuki Numata

INTERNAL MEDICINE 45 ( 9 ) 599 - 603 2006

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

Objective We investigated the link between metabolic syndrome and proteinuria in Japanese.
Methods A total of 12,023 Japanese subjects, aged 20-79 years, were recruited in a cross-sectional clinical investigation study. From this group, we used data of 2,121 subjects for further investigation. Proteinuria was measured by using urine strip devices. The diagnosis of metabolic syndrome was based on the new criterion in Japan.
Results In the first analysis, 224 men (6.0%) and 359 women (4.3%) were diagnosed as trace positive (+/-) and 155 men (4.1%) and 147 women (1.8%) were diagnosed as positive (+<=) with proteinuria. In the second analysis, 264 men (29.7%) and 45 women (3.7%) were diagnosed as metabolic syndrome. Prevalence of proteinuria in subjects with metabolic syndrome was significantly higher than that in subjects with non metabolic syndrome in both sexes. In addition, the atherogenic index was significantly higher in subjects with metabolic syndrome than in subjects with non-metabolic syndrome.
Conclusion The present study indicated that metabolic syndrome might be an important factor in the etiology of proteinuria in Japanese.

DOI： 10.2169/internalmedicine.45.1681

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Molecular biology of regulation in renal functions; biosynthesis, metabolism, and action of insulin and glucagon

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

Nippon rinsho. Japanese journal of clinical medicine 64 Suppl 2 2006

ACAM, vaspin

Wada, J., Hida, K., Eguchi, J., Makino, H.

Nippon rinsho. Japanese journal of clinical medicine 64 Suppl 9 2006

The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation Reviewed

K Fukui, Q Yang, Y Cao, N Takahashi, H Hatakeyama, HY Wang, J Wada, YL Zhang, L Marselli, T Nammo, K Yoneda, M Onishi, S Higashiyama, Y Matsuzawa, FJ Gonzalez, GC Weir, H Kasai, L Shimomura, J Miyagawa, CB Wollheim, K Yamagata

CELL METABOLISM 2 ( 6 ) 373 - 384 2005.12

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

Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1 alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1 alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1 alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca2+ influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.

DOI： 10.1016/j.cmet.2005.11.003

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Long-term use of vitamin E-coated polysulfone membrane reduces oxidative stress markers in haemodialysis patients Reviewed

H Morimoto, K Nakao, K Fukuoka, A Sarai, A Yano, T Kihara, S Fukuda, J Wada, H Makino

NEPHROLOGY DIALYSIS TRANSPLANTATION 20 ( 12 ) 2775 - 2782 2005.12

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

Background. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and an independent predictor of overall mortality and cardiovascular outcome in haemodialysis (HD) patients. In the present study, we compared the effects of a vitamin E-coated polysulfone membrane (PSE) and a non-vitamin E-coated polysulfone membrane (PS) on oxidative stress markers such as ADMA.
Methods. Thirty-one HD patients were enrolled to this investigation. They were allocated into two groups: in the PSE group (n = 16), PSE was used for 6 months, followed by PS for an additional 12 months; in the PS group (n = 15), PS was used for the entire observation period. Plasma ADMA, oxidized low density lipoprotein (Ox-LDL) and malondialdehyde LDL (MDA-LDL) levels were measured at baseline, 3, 6, 12 and 18 months. Plasma ADMA in peritoneal dialysis (PD) patients and in healthy individuals was also measured.
Results. Predialysis concentrations of ADMA (0.72 +/- 0.13 nmol/ml) were significantly higher in the HD group than in both PD patients (0.63 +/- 0.10 nmol/ml, P < 0.01) and healthy individuals (0.44 +/- 0.01 nmol/ml, P < 0.0001). Treatment with PSE for 6 months significantly reduced predialysis levels of ADMA (0.54 +/- 0.09 nmol/ml) compared with baseline (0.74 +/- 0.12 nmol/ml; P < 0.01). Predialysis levels of Ox-LDL and MDA-LDL after 6 months therapy with PSE were also significantly lower than baseline values. Treatment with PS subsequent to treatment with PSE again increased ADMA, Ox-LDL and MDA-LDL back to baseline levels. In the PS group, ADMA, Ox-LDL and MDA-LDL levels remained unchanged during the entire treatment period of 18 months.
Conclusions. We confirmed that use of PSE reduced ADMA that had accumulated in HD patients. This finding indicates that PSE exerts anti-oxidant activity. A randomized controlled study will be required to determine whether PSE prevents cardiovascular diseases and other dialysis-related complications by reducing oxidative stress.

DOI： 10.1093/ndt/gfi121

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Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience Reviewed

B Nayak, P Xie, S Akagi, QW Yang, L Sun, J Wada, A Thakur, FR Danesh, SS Chugh, YS Kanwar

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 102 ( 50 ) 17952 - 17957 2005.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Biological properties of renal-specific oxicloreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to D-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerol phosphoryl-choline and H2O2. Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.

DOI： 10.1073/pnas.0509089102

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Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes Reviewed

A Nakamura, K Shikata, M Hiramatsu, T Nakatou, T Kitamura, J Wada, T Itoshima, H Makino

DIABETES CARE 28 ( 12 ) 2890 - 2895 2005.12

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

OBJECTIVE - interleukin (IL)- 18 is a proinflammatory cytokine secreted from mononuclear cells. Serum concentration of IL-18 is a strong predictor of death in patients with cardiovascular diseases. Recent studies have shown that microinflammation is involved in the pathogenesis of diabetic nephropathy as well as of cardiovascular diseases. This study aimed to test the hypothesis that the serum level of IL-18 is a common predictor of nephropathy and atherosclerosis in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS - Eighty-two Japanese patients with type 2 diabetes and 55 age- and sex-matched healthy control subjects were enrolled. Patients With renal dysfunction (creatinine clearance < 1 ml/s) were excluded. We assessed clinical parameters and measured serum and urinary IL-18 levels, serum IL-6 levels, Carotid intima-media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in all patients. Further, we evaluated changes of urinary albumin excretion rate (AER) after 6 months in 76 diabetic patients.
RESULTS - Serum and urinary IL-18 levels were significantly elevated in patients with type 2 diabetes as compared with control subjects (serum IL-18 179 62 vs. 121 - 55 pg/ml, P < 0.001; urinary IL-18 97 - 159 vs. 47 - 54 pg/ml, P = 0.035). Univariate linear regression analysis showed significant positive correlations between serum IL- 18 and AER (r [correlation coefficient] = 0.525, P < 0.001), HbA(1C) (r = 0.242, P = 0.029), high-sensitivity C-reactive protein (hs-CRP) (r = 0.240, P = 0.031), and urinary beta-2 microglobulin (r = 0.235, P = 0.036) Serum IL-18 levels also correlated positively with carotid IMT (r = 0.225, P = 0.042) and baPWV (r = 0.232, P = 0.040). We also found a significant correlation between urinary IL-18 and AER (r = 0.309, P = 0.005). Multivariate linear regression analysis showed that AER (standard correlation coefficients [B] = 0.405, P < 0.001) and hs-CPP (B = 0.207, P = 0.033) were independently associated with serum IL- 18 levels. AER was also independently associated with urinary IL-18 levels (B = 0.295, P = 0.005). Moreover, serum and urinary IL-18 levels correlated positively with AER after 6 months (r = 0.489, P < 0.001 and r = 0.320, P - 0.005) and changes in AER during the follow-up period (r = 0.268, P = 0.018 and r = 0.234, P = 0.042).
CONCLUSIONS - Serum levels of IL- 18 might be a predictor of progression of diabetic nephropathy as well as cardiovascular diseases.

DOI： 10.2337/diacare.28.12.2890

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Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions Reviewed

K Yozai, K Shikata, M Sasaki, A Tone, S Ohga, H Usui, S Okada, J Wada, R Nagase, D Ogawa, Y Shikata, H Makino

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 16 ( 11 ) 3326 - 3338 2005.11

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

Recent studies suggested the involvement of inflammatory processes in the pathogenesis of diabetic nephropathy. Methotrexate (MTX), a folic acid antagonist, is widely used for the treatment of inflammatory diseases. Recently, it has been shown that treatment with low-dose MTX reduces the cardiovascular mortality in patients with rheumatoid arthritis, suggesting that MTX has anti-atherosclerotic effects via its anti-inflammatory actions. This study was designed to determine the anti-inflammatory effects of this agent on diabetic nephropathy. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and MTX (0.5 or 1.0 mg/kg) was administered once a week for 8 wk. Treatment with MTX reduced urinary albumin excretion, mesangial matrix expansion, macrophage infiltration, expression of TGF-beta and type IV collagen, and intercellular adhesion molecule-1 in glomeruli. MTX also reduced the high glucose-induced NF-kappa B activation in vitro and in vivo. The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats. The protective effects of MTX are suggested to be mediated by its anti-inflammatory actions through inhibition of NF-kappa B activation and consequent reduction of intercellular adhesion molecule-1 expression and macrophage infiltration. The results suggest that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.

DOI： 10.1681/ASN.2004111011

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Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats Reviewed

A Tone, K Shikata, M Sasaki, S Ohga, K Yozai, S Nishishita, H Usui, R Nagase, D Ogawa, S Okada, Y Shikata, J Wada, H Makino

DIABETOLOGIA 48 ( 11 ) 2402 - 2411 2005.11

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

Aims/hypothesis: Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats. Methods: STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-kB) activity. Results: Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-b1), type IV collagen protein production and NF-kB activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment. Conclusions/interpretation: Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF- activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.

DOI： 10.1007/s00125-005-1945-6

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Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms Reviewed

M Baba, J Wada, J Eguchi, Hashimoto, I, T Okada, A Yasuhara, K Shikata, YS Kanwar, H Makino

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 16 ( 11 ) 3222 - 3234 2005.11

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

Galectins are beta-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CD8(+) T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on G1-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-beta 1 and the number of p27(Kip1)- and p21(Cip1)-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27(kip1). For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 MM D-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27(Kip1) and p21(Cip1) and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [H-3]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-beta 1 and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward. diabetic nephropathy.

DOI： 10.1681/ASN.2004110915

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