Faculty Profiles - WADA Jun

Papers - WADA Jun

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Gene delivery of Tim44 reduces mitochondrial superoxide production and ameliorates neointimal proliferation of injured carotid artery in diabetic rats Reviewed

T Matsuoka, J Wada, Hashimoto, I, YL Zhang, J Eguchi, N Ogawa, K Shikata, YS Kanwar, H Makino

DIABETES 54 ( 10 ) 2882 - 2890 2005.10

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

Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane (Tim)44 was identified by upregulation in streptozotocin (STZ)-induced diabetic mouse kidneys; Tim44 functions as a membrane anchor of mtHsp70 to TIM23 complex and is involved in the import of preproteins with mitochondria-targeted presequence into mitochondrial matrix. The process is dependent on inner membrane potential (Delta psi) and ATP hydrolysis on ATPase domain of mtHsp70. Here, we show that the gene delivery of Tim44 using pcDNA3.1 vector (pcDNA3.1/TIM44) into the balloon injury model of STZ-induced diabetic rats ameliorated neointinial proliferation. ROS production, inflammatory responses, and cell proliferation in injured carotid artery were diminished by delivery of pcDNA3.1/ TIM44. In vitro experiments using human aortic smooth muscle cells (HASMCs) revealed that the gene delivery of Tim.44 normalized high-glucose-induced enhanced ROS production and increased ATP production, alterations in inner membrane potential, and cell proliferation. Transfection of siRNA and pcDNA3.1/TIM44 using HASMC culture clarified that import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase was facilitated by Tim44. Tim44 and its related molecules in mitochondrial import machinery complex are novel targets in the therapeutic interventions for diabetes and its vascular complications.

DOI： 10.2337/diabetes.54.10.2882

Renal-specific oxidoreductase biphasic expression under high glucose ambience during fetal versus neonatal development Reviewed

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

KIDNEY INTERNATIONAL 68 ( 4 ) 1670 - 1683 2005.10

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

Renal-specific oxidoreductase biphasic expression under high glucose ambience during fetal vs. neonatal development.
Background. Renal-specific oxidoreductase (RSOR) has been recently identified in mice kidneys of diabetic animals, and it is developmentally regulated. Its expression during fetal, neonatal, and postnatal periods was assessed under high glucose ambience.
Methods. Whole-mount immunofluorescence and confocal microscopy were performed to assess the effect of high glucose on the morphogenesis of mice fetal kidneys. RSOR mRNA and protein expression was assessed by competitive polymerase chain reaction (PCR) and immunoprecipitation methods in embryonic kidneys (day E13 to E17) subjected to high glucose ambience and by Northern and Western blot analyses of kidneys of newborn and 1-week-old mice with hyperglycemia. The spatiotemporal changes in the RSOR expression were assessed by in situ hybridization analyses and immunofluorescence microscopy. In addition, the extent of apoptosis in the kidneys was determined by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay.
Results. Whole-mount microscopy of the embryonic metanephroi revealed a dose-dependent disruption in the ureteric bud iterations with reduced population of the nascent nephrons. Both gene and protein expressions were reduced in day E13 to E17 metanephroi, while increased in kidneys of newborn and 1-week-old mice. In day E13 and day E15 kidneys, the RSOR was expressed in the ureteric bud branches and some of the immature tubules, and its expression was reduced with high glucose treatment. In day E17 kidneys the RSOR was expressed in the tubules of the deeper cortex, and its expression was marginally decreased. In newborn kidneys, this enzyme was expressed in the subcortical tubules and it spread to the entire width of the renal cortex in hyperglycemic state. In 1-week-old mice kidneys, the RSOR was localized to the entire cortex, and in animals with blood glucose above 300 mg/dL, its intensity increased with extension of expression into the outer medullary tubules. A dose-dependent fulminant apoptosis was observed in day E13 to E17 kidneys subjected to high glucose ambience. In newborn and 1-week-old mice control kidneys, the apoptosis was minimal although slightly increased during hyperglycemia.
Conclusion. High glucose has a differential effect on the RSOR expression in kidneys during the embryonic versus neonatal/postnatal period. This may partly be related to the differential degree of apoptosis, a process reflective of oxidant stress that is seen in diabetic milieu, which as previously has been shown to adversely effect the modulators of fetal development and thereby the morphogenesis of the kidney and RSOR expression.

DOI： 10.1111/j.1523-1755.2005.00611.x

Clinical features of non-diabetic renal diseases in patients with type 2 diabetes Reviewed

A Tone, K Shikata, M Matsuda, H Usui, S Okada, D Ogawa, J Wada, H Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 69 ( 3 ) 237 - 242 2005.9

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

Although persistent proteinuria is characteristic of diabetic nephropathy (DN), it is important to differentiate non-diabetic renal diseases (NDRD) in diabetic patients with proteinuria. In order to re-evaluate the indications for renal biopsy in the diabetic patients, we retrospectively analyzed the relationship between clinical features and histological diagnosis in 97 Japanese patients with type 2 diabetes manifesting overt proteinuria. Renal biopsy was performed because they were clinically suspected to have NDRD. Patients were divided into three groups according to the histological diagnosis: (1) the DN group (n = 35) had only diabetic lesions, (2) the complicated group (n = 16) had histological changes of NDRD superimposed on DN and (3) the non-DN group (n = 46) had NDRD without diabetic lesions. We evaluated the specificity and sensitivity of four clinical parameters (duration of diabetes, presence or absence of diabetic retinopathy, microscopic hematuria and granular casts as urinary sediments) for the prediction of NDRD. Short duration of diabetes (< 5 years) showed high sensitivity (75%) and specificity (70%). Diabetic retinopathy showed the highest sensitivity (87%) and specificity (93%). The sensitivity and specificity of microscopic hematuria (56 and 58%) and granular casts (68 and 47%) were lower. Our study confirmed that the absence of retinopathy and short duration of diabetes are useful clinical indications for renal biopsy in diabetic patients with overt protemuria. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2005.02.009

Hyperglycemia: its imminent effects on mammalian nephrogenesis Reviewed

YS Kanwar, B Nayak, S Lin, S Akagi, P Xie, J Wada, SS Chugh, FR Danesh

PEDIATRIC NEPHROLOGY 20 ( 7 ) 858 - 866 2005.7

Language：English Publisher：SPRINGER

A sustained exposure of the mammalian embryo to very high glucose ambience is associated with a multitude of congenital birth defects, including those of the cardiovascular, CNS, skeletal and urogenital systems during the first 6 - 8 weeks of gestation in humans. These urogenital abnormalities may be associated with "caudal regression syndrome" or may occur alone in the form of partial or total renal agenesis. Similarly, an increase in the incidence of morphogenetic defects is observed in the offspring of streptozotocin-induced diabetic rats and mice, and also in non- obese diabetic mice. In certain cases, failure during the growth of the lower parts of embryos or newborn mice involving the genitourinary system has been observed in animals with severe diabetes. Investigators have utilized whole organ culture systems to delineate the mechanisms relevant to dysmorphogenesis of the embryonic metanephros. A marked dysmorphogenesis of the metanephros is observed upon treatment with a high concentration of D-glucose. Associated with it are changes that include branching dysmorphogenesis of the ureteric bud iterations, reduced population of nascent nephrons, decreased expression of basement membrane proteoglycans, depletion of ATP stores, and fulminant apoptosis of the cells at the interface of mesenchyme and ureteric bud epithelium. The latter findings suggest that disruption of epithelial: mesenchymal interactions may be the major event responsible for the metanephric dysmorphogenesis induced by high glucose ambience.

DOI： 10.1007/s00467-005-1888-7

Visceral adipose tissue-derived serine protease inhibitor: A unique insulin-sensitizing adipocytokine in obesity Reviewed

K Hida, J Wada, J Eguchi, H Zhang, M Baba, A Seida, L Hashimoto, T Okada, A Yasuhara, A Nakatsuka, K Shikata, S Hourai, J Futami, E Watanabe, Y Matsuki, R Hiramatsu, S Akagi, H Makino, YS Kanwar

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 102 ( 30 ) 10610 - 10615 2005.7

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

There is a rapid global rise in obesity, and the link between obesity and diabetes remains somewhat obscure. We identified an adipocytokine, designated as visceral adipose tissue-derived serpin (vaspin), which is a member of serine protease inhibitor family. Vaspin cDNA was isolated by from visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETIF) rat, an animal model of abdominal obesity with type 2 diabetes. Rat, mouse, and human vaspins are made up of 392,394, and 395 amino acids, respectively; exhibit approximate to 40% homology with alpha(1)-antitrypsin; and are related to serine protease inhibitor family. Vaspin was barely detectable in rats at 6 wk and was highly expressed in adipocytes of visceral WATs at 30 wk, the age when obesity, body weight, and insulin levels peak in OLETF rats. The tissue expression of vaspin and its serum levels decrease with worsening of diabetes and body weight loss at 50 wk. The expression and serum levels were normalized with the treatment of insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats. Administration of vaspin to obese CRL:CD-1 (ICR) (ICR) mice fed with high-fat high-sucrose chow improved glucose tolerance and insulin sensitivity reflected by normalized serum glucose levels. It also led to the reversal of altered expression of genes relevant to insulin resistance, e.g., leptin, resistin, TNF alpha, glucose transporter-4, and adiponectin. In DNA chip analyses, vaspin treatment resulted in the reversal of expression in approximate to 50% of the high-fat high-sucrose-induced genes in WATs. These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity.

DOI： 10.1073/pnas.0504703102

Identification of adipocyte adhesion molecule (ACAM), a novel CTX gene family, implicated in adipocyte maturation and development of obesity Reviewed

J Eguchi, J Wada, K Hida, H Zhang, T Matsuoka, M Baba, Hashimoto, I, K Shikata, N Ogawa, H Makino

BIOCHEMICAL JOURNAL 387 343 - 353 2005.4

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

Few cell adhesion molecules have been reported to be expressed in mature adipocytes, and the significance of cell adhesion process in adipocyte biology is also unknown. In the present study, we identified ACAM (adipocyte adhesion molecule), a novel homologue of the CTX (cortical thymocyte marker in Xenopus) gene family. ACAM cDNA was isolated during PCR-based cDNA subtraction, and its mRNA was shown to be up-regulated in WATs (white adipose tissues) of OLETF (Otsuka Long-Evans Tokushima fatty) rats, an animal model for Type II diabetes and obesity. ACAM, 372 amino acids in total, has a signal peptide, V-type (variable) and C2-type (constant) Ig domains, a single transmembrane segment and a cytoplasmic tail. The amino acid sequence in rat is highly homologous to mouse (94%) and human (87%). ACAM mRNA was predominantly expressed in WATs in OLETF rats, and increased with the development of obesity until 30 weeks of age, which is when the peak of body mass is reached. Western blot analysis revealed that ACAM protein, approx. 45 kDa, was associated with plasma membrane fractions of mature adipocytes isolated from mesenteric and subdermal adipose deposits of OLETF rats. Up-regulation of ACAM mRNAs in obesity was also shown in WATs of genetically obese db/db mice, diet-induced obese ICR mice and human obese subjects. In primary cultured mouse and human adipocytes, ACAM mRNA expression was progressively up-regulated during differentiation. Several stably transfected Chinese-hamster ovary K1 cell lines were established, and the quantification of ACAM mRNA and cell aggregation assay revealed that the degree of homophilic aggregation correlated well with ACAM mRNA expression. In summary, ACAM may be the critical adhesion molecule in adipocyte differentiation and development of obesity.

DOI： 10.1042/BJ20041709

Cell biology of diabetic kidney disease

Kanwar, YS, Akagi, S, Sun, L, Nayak, B

Nephron Experimental Nephrology 101 ( 3 ) 2005

Sulfated hyaluronic acid, a potential selectin inhibitor, ameliorates experimentally induced crescentic glomerulonephritis Reviewed

D Ogawa, K Shikata, M Matsuda, K Akima, M Iwahashi, S Okada, Y Tsuchiyama, Y Shikata, J Wada, H Makino

NEPHRON EXPERIMENTAL NEPHROLOGY 99 ( 1 ) E26 - E32 2005

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

Background/Aims: Sulfated polysaccharides are known to interfere with the binding of selectins and their ligands. Recently, we demonstrated that sulfated hyaluronic acid (SHA), a synthetic sulfated polysaccharide, showed preventive and therapeutic effects on experimental mesangial proliferative glomerulonephritis. Here we evaluated the protective potential of SHA on crescentic glomerulonephritis, using nephrotoxic serum (NTS) nephritis in Wistar-Kyoto (WKY) rats. Methods: Crescentic glomerulonephritis was induced by injection of NTS in WKY rats. Rats subsequently received intraperitoneal administration of SHA (0.5 or 1.5 mg/kg/day) or non-sulfated hyaluronic acid ( HA) ( 1.5 mg/kg/day) for 14 days. The urinary protein excretion was measured, and expression of selectins, intraglomerular leukocytes and crescent formation were examined by immunohistochemistry. In addition, we examined the urinary protein excretion of SHA ( 1.5 mg/kg/day) administered from day 7 after the induction of crescentic glomerulonephritis. Results: The expression of P-selectin was increased in the glomerulus of crescentic glomerulonephritis. SHA reduced proteinuria, macrophage infiltration, and crescent formation in a dose-dependent manner. Furthermore, administration of SHA ( 1.5 mg/kg/day) from day 7 also reduced the urinary protein excretion on day 14 compared with that in saline and HA group. Conclusion: Our results suggest that SHA inhibits intraglomerular infiltration of macrophages, and prevents progression of experimental crescentic glomerulonephritis. Sulfated polysaccharides might be beneficial for the treatment of crescentic glomerulonephritis. Copyright (C) 2005 S. Karger AG, Basel.

DOI： 10.1159/000081795

Pathological roles of advanced glycation end product receptors SR-A and CD36 Reviewed

S Horiuchi, Y Unno, H Usui, K Shikata, K Takaki, W Koita, YI Sakamoto, R Nagai, K Makino, A Sasao, J Wada, H Makino

MAILLARD REACTION: CHEMISTRY AT THE INTERFACE OF NUTRITION, AGING, AND DISEASE 1043 671 - 675 2005

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

The pathological significance of advanced glycation end product (AGE)-modified proteins deposited in several lesions is generally accounted for by their cellular interaction via the AGE receptors and subsequent acceleration of the inflammatory process. In this study, we focused on two AGE receptors-specifically, the role of SR-A in pathogenesis of diabetic nephropathy and the role of CD36 in AGE-induced downregulation of leptin by adipocytes. In terms of SR-A, diabetic wild-type mice exhibited increased urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion, whereas SR-A-knockout mice showed reduced glomerular size and mesangial matrix area. In these diabetic SR-A-knockout mice, the number of macrophages that infiltrated into glomeruli was remarkably reduced (P < 0.05), suggesting that SR-A-dependent glomerular migration of macrophages plays an important role in the pathogenesis of diabetic nephropathy. In terms of CD36, incubation of glycolaldehyde-modified bovine serum albumin (GA-BSA) with 3T3-L1 adipocytes reduced leptin secretion by these cells. The binding of GA-BSA to these cells and subsequent endocytic degradation were effectively inhibited by a neutralizing anti-CD36 antibody. AGE-induced downregulation of leptin was protected by N-acetyl-cysteine, an antioxidant. These results indicate that the interaction of AGE ligands with 3T3-L1 adipocytes via CD36 induces oxidative stress and leads to inhibition of leptin expression by these cells, suggesting a potential link of this phenomenon to exacerbation of the insulin sensitivity in metabolic syndrome.,

DOI： 10.1196/annals.1333.076

Cell biology of diabetic kidney disease

Kanwar, Y.S., Akagi, S., Sun, L., Nayak, B., Xie, P., Wada, J., Chugh, S.S., Danesh, F.R.

Nephron - Experimental Nephrology 101 ( 3 ) 2005

The critical role of Src homology domain 2-containing tyrosine phosphatase-1 in recombinant human erythropoietin hyporesponsive anemia in chronic hemodialysis patients Reviewed

S Akagi, H Ichikawa, T Okada, A Sarai, T Sugimoto, H Morimoto, T Kihara, A Yano, K Nakao, Y Nagake, J Wada, H Makino

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 15 ( 12 ) 3215 - 3224 2004.12

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

The molecular mechanism of anemia that is hyporesponsive to recombinant human erythropoietin (rHuEPO) in hemodialysis patients without underlying causative factors has not been investigated fully in hematopoietic stem cell system. Circulating CD34+ cells (l x: 10(4)) were isolated from rHuEPO hyporesponsive hemodialysis patients (EPO-H; n. = 9), patients who were responsive to rHuEPO (EPO-R; n = 9), and healthy control subjects (n = 9). The patients with known causes of EPO hyporesponsiveness were eliminated from the current study. The cells were cultured in STEM PRO 34 liquid medium, supplemented with rHUEPO,IL-3, stern cell factor, and granulocyte-macrophage colony stimulating factor for 7 d and then transferred to a semisolid methylcellulose culture medium for performing burst forming unit-erythroid (BFU-E) colony assay. Expression of src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP1), phosphotylated Janus kinase 2 (p-JAK2), and phosphotylated signal transducer and aclivator of transcription 5 (p-STAT5) was assessed with Western blot analysis. In EPO-H patients, SHP-l antisense or scrambled S-oligos were included in the culture medium, and its effects were evaluated. The number of circulating CD34+ cells was not statistically different among the three groups, and their proliferation rates were similar for 7 d in culture. However, BFU-E colonies were significantly decreased in EPO-H patients compared with EPO-R and control groups. The mRNA and protein expression of SHP-I and p-SHP-1 was significantly increased, whereas that of p-STAT5 was reduced in EPO-H patients. The inclusion of SHP-1 antisense S-oligo in culture suppressed SHP-1 protein expression associated with p-STAT5 upregulation, increase in p-STAT5-regulated genes, and partial recovery of BFU-E colonies. In EPO-H hemodialysis patients, the EPO signaling pathway is attenuated as a result of dephosphotylation of STAT5 via upregulation of SHP-I phosphatase activity, and SHP-I may be a novel target molecule to sensitize EPO action in these patients.

DOI： 10.1097/01.ASN.0000145457.73744.24

Changes in serum leptin concentrations in overweight Japanese men after exercise Reviewed

N Miyatake, K Takahashi, J Wada, H Nishikawa, A Morishita, H Suzuki, M Kunitomi, H Makino, S Kira, M Fujii

DIABETES OBESITY & METABOLISM 6 ( 5 ) 332 - 337 2004.9

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

Aim: To investigate the link between serum leptin concentrations and exercise.
Design: Cross-sectional and longitudinal studies of an exercise intervention.
Subjects: 110 Japanese overweight men aged 32-59 years were recruited. At baseline, the average body mass index (BMI) was 28.5 +/- 2.5 kg/m(2). From this group, we used data of 36 overweight men (BMI, 28.9 +/- 2.3) for a 1-year exercise programme.
Measurements: Leptin was measured at baseline and after 1 year. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical levels. Anthropometric parameters, aerobic exercise level, muscle strength and flexibility were also investigated at baseline and after 1 year.
Results: In the first analysis, using cross-sectional data, leptin was significantly correlated with total body fat (r = 0.760, p < 0.01), V (r = 0.383, p < 0.01) and S (r = 0.617, p < 0.01) areas. In the second analysis, using longitudinal data, leptin was significantly reduced after 1 year (pre 6.7 +/- 4.0 ng/ml vs. post 5.1 +/- 3.1 ng/ml, p < 0.01). Results showed that steps per day were increased, and aerobic exercise level, weight-bearing index (WBI) and insulin resistance were significantly improved. Although, there was a positive correlation between A leptin(positive changes in leptin after 1 year) and anthropometric measurements such as Delta body weight, Delta BMI and Delta body fat, leptin/body weight, leptin/BMI and leptin/body fat ratios were significantly reduced during exercise intervention.
Conclusion: The present study indicated exercise significantly lowers serum leptin concentrations, and thus it may improve the leptin resistance observed in overweight Japanese men.

DOI： 10.1111/j.1462-8902.2004.00351.x

Update of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis Reviewed

YS Kanwar, J Wada, S Lin, FR Danesh, SS Chugh, QW Yang, T Banerjee, JW Lomasney

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 286 ( 2 ) F202 - F215 2004.2

Language：English Publisher：AMER PHYSIOLOGICAL SOC

One of the hallmarks of mammalian nephrogenesis includes a mesenchymalepithelial transition that is accomplished by intercalation of the ureteric bud, an epithelium-lined tubelike structure, into an undifferentiated mesenchyme, and the latter then undergoes an inductive transformation and differentiates into an epithelial phenotype. At the same time, the differentiating mesenchyme reciprocates by inducing branching morphogenesis of the ureteric bud, which forms a treelike structure with dichotomous iterations. These reciprocal inductive interactions lead to the development of a functioning nephron unit made up of a glomerulus and proximal and distal tubules. The inductive interactions and differentiation events are modulated by a number of transcription factors, protooncogenes, and growth factors and their receptors, which regulate the expression of target morphogenetic modulators including the ECM, integrin receptors, and cell adhesion molecules. These target macromolecules exhibit spatiotemporal and stage-specific developmental regulation in the metanephros. The ECM molecules expressed at the epithelial-mesenchymal interface are perhaps the most relevant and conducive to the paracrine-juxtacrine interactions in a scenario where the ligand is expressed in the mesenchyme while the receptor is located in the ureteric bud epithelium or vice versa. In addition, expression of the target ECM macromolecules is regulated by matrix metalloproteinases and their inhibitors to generate a concentration gradient at the interface to further propel epithelial-mesenchymal interactions so that nephrogenesis can proceed seamlessly. In this review, we discuss and update our current understanding of the role of the ECM and related macromolecules with respect to metanephric development.

DOI： 10.1152/ajprenal.00157.2003

The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats Reviewed

K Hiragushi, J Wada, J Eguchi, T Matsuoka, A Yasuhara, Hashimoto, I, T Yamashita, K Hida, Y Nakamura, K Shikata, N Minamino, K Kangawa, H Makino

KIDNEY INTERNATIONAL 65 ( 2 ) 540 - 550 2004.2

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

Background. Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy.
Methods. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release.
Results. STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, D-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides.
Conclusion. Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.

DOI： 10.1111/j.1523-1755.2004.00407.x

Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction Reviewed

D Ogawa, K Shikata, K Honke, S Sato, M Matsuda, R Nagase, A Tone, S Okada, H Usui, J Wada, M Miyasaka, H Kawashima, Y Suzuki, T Suzuki, N Taniguchi, Y Hirahara, K Tadano-Aritomi, Ishizuka, I, TF Tedder, H Makino

JOURNAL OF BIOLOGICAL CHEMISTRY 279 ( 3 ) 2085 - 2090 2004.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide-and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst(-/-) mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wildtype mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst(-/-) mice irrespective of UUO treatment. Compared with wild-type mice, Cst(-/-) mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin(-/-) mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium.

DOI： 10.1074/jbc.M305809200

Multicentric Castleman's disease associated with glomerular microangiopathy and MPGN-like lesion: Does vascular endothelial cell-derived growth factor play causative or protective roles in renal injury? Reviewed

A Seida, J Wada, Y Morita, M Baba, J Eguchi, N Nishimoto, T Okino, K Ichimura, T Yoshino, H Makino

AMERICAN JOURNAL OF KIDNEY DISEASES 43 ( 1 ) 2004.1

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

A 52-year-old Japanese man presented with fever spikes, generalized fatigue, anorexia, and anasarca. The patient was referred for the evaluation of fever of unknown origin in association with swelling of cervical, axillary, and inguinal lymph nodes. He also manifested nephrotic syndrome, acute renal failure, hepatosplenomegaly, massive pleural effusion, ascites, disseminated intravascular coagulation, and hypergammaglobulinemia. C-reactive protein was positive and plasma vascular endothelial cell-derived growth factor (VEGF) and serum interleukin-6 levels were markedly elevated. Lymph node biopsy results showed that findings were compatible with Castleman's disease of hyaline vascular type associated with interfollicular plasmacytosis. In conjunction with the clinical findings, a diagnosis of multicentric Castleman's disease was made. The patient underwent renal biopsy because of nephrotic syndrome, and the results showed proliferation of mesangial cells, lobulation of glomeruli, and tram track pattern of the capillary wall without immune complex deposition. Electron microscopy showed widening of the subendothelial space. No electron-dense deposits were present in both mesangial and subendothelial regions. Pathologic features were compatible with glomerular microangiopathy and membranoproliferative glomerulonephritis-like lesions. With corticosteroid therapy, systemic symptoms disappeared; both VEGF and interleukin-6 levels were normalized, and he went into complete remission of nephrotic syndrome. In this article, the role VEGF plays in the pathogenesis of nephrotic syndrome and glomerular microangiopathy is discussed.

DOI： 10.1053/j.ajkd.2003.09.023

Intravenous vitamin D therapy reduces PTH-(1-84)/large C fragments ratio in chronic hemodialysis patients Reviewed

T Kihara, H Ichikawa, H Morimoto, A Yano, S Akagi, K Nakao, H Kohmoto, J Wada, Kumagai, I, H Makino

NEPHRON CLINICAL PRACTICE 98 ( 3 ) C93 - C100 2004

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

Background: Renal osteodystrophy is one of the major complications in patients with chronic renal failure. Large C-PTH fragments are secreted from the parathyroid glands and exert antagonistic actions against PTH( 1 - 84). The PTH-(1 - 84)/ large C-PTH fragments ratio reflects both biosynthesis and processing of PTH; however the alteration of the ratio under vitamin D therapy has not been investigated. Methods: Seventeen hemodialysis patients with intact PTH levels of > 300 pg/ml were enrolled. Calcitriol or maxacalcitol were administered intravenously for 78 weeks. Intact PTH, PTH-( 1 - 84), and the PTH-( 1 - 84)/ large C-PTH fragments ratio were measured at 0, 13, 26, 52 and 78 weeks. Results: Intact PTH and PTH-(1 - 84) levels, which were 492.0 +/- 115.7 and 303.4 +/- 105.4 pg/ml, respectively, at baseline, significantly decreased at the end of the study to 268.9 +/- 121.9 ( p < 0.0001) and 190.7 +/- 106.9 pg/ml ( p = 0.0008), respectively. In contrast, large C-PTH fragments, which were 152.7 +/- 53.5 pg/ml at baseline, did not significantly change at 78 weeks (144.5 +/- 72.2 pg/ml, p = 0.7612). Consequently, the PTH-(1 - 84)/ large C-PTH fragments ratio was significantly reduced from 2.25 +/- 1.31 to 1.47 +/- 0.89 (p = 0.0004). Conclusion: The PTH-(1-84)/ large CPTH fragments ratio reflects the change of PTH biosynthesis, processing and secretion from the parathyroid glands, and it may be a beneficial marker to evaluate the overall biological PTH action and predict bone turnover status in hemodialysis patients under intravenous vitamin D therapy. Copyright (C) 2004 S. Karger AG, Basel.

DOI： 10.1159/000080680

Multicentric Castleman's disease associated with glomerular microangiopathy and MPGN-like lesion: does vascular endothelial cell-derived growth factor play causative or protective roles in renal injury?

Seida, A., Wada, J., Morita, Y., Baba, M., Eguchi, J., Nishimoto, N., Okino, T., Ichimura, K., Yoshino, T., Makino, H.

American journal of kidney diseases : the official journal of the National Kidney Foundation 43 ( 1 ) 2004

Daily exercise lowers blood pressure and reduces visceral adipose tissue areas in overweight Japanese men Reviewed

N Miyatake, K Takahashi, J Wada, H Nishikawa, A Morishita, H Suzuki, M Kunitomi, H Makino, S Kira, M Fujii

DIABETES RESEARCH AND CLINICAL PRACTICE 62 ( 3 ) 149 - 157 2003.12

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

Objective: To investigate the link between a reduction in blood pressure (BP) and daily exercise. Design: Cross-sectional and longitudinal clinical intervention study with exercise education. Subjects: 43 overweight Japanese men aged 32-59 years (BMI, 29.0+/-2.3 kg/m(2)) at baseline. Among the participants, a randomly selected 23 overweight men (BMI, 28.5+/-1.7) were further enrolled into the 10 months exercise program. Measurements: BP was measured every week and steps per day were also recorded every day throughout the observation period. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical level, at before, 5 months and after intervention. Anthropometric parameters were also measured at same point. Aerobic exercise level, muscle strength, flexibility and calorie intake and insulin resistance (HOMA index) were investigated at before and after the study. Results: In a cross sectional analysis, systolic BP (SBP) and diastolic BP (DBP) were significantly correlated with body composition. In a second longitudinal analysis, SBP was significantly reduced at 2 months and DBP was also reduced at 3 months, and almost maintained until the end of the observation period. Increasing daily walking was observed in 3 months and maintained until 10 months. Body composition, aerobic exercise level, muscle strength, flexibility and insulin resistance were significantly improved. There was positive correlation between DeltaDBP and Deltavisceral fat area (1-5, 5-10, 1-10 months). By stepwise multiple regression analysis, only Deltavisceral fat area was independently related to DeltaDBP at a significant level (1-10 months: DeltaDBP=-0.608+0.105Deltavisceral fat area, r(2)=0.227, P=0.0334). Conclusion: The present study indicated daily exercise lowers BP and visceral fat area is the critical factor for BP change. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/S0168-8227(03)00176-1

Serum bFGF levels are reduced in Japanese overweight men and restored by a 6-month exercise education Reviewed

A Seida, J Wada, M Kunitomi, Y Tsuchiyama, N Miyatake, M Fujii, S Kira, K Takahashi, K Shikata, H Makino

INTERNATIONAL JOURNAL OF OBESITY 27 ( 11 ) 1325 - 1331 2003.11

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

OBJECTIVE: To investigate whether the changes in vascular endothelial growth factor ( VEGF) and basic fibroblast growth factor ( bFGF) concentrations before and after weight reduction in Japanese overweight men are associated with changes in body mass index (BMI), visceral, subcutaneous fat, VO2 and work rate (WR) at ventilatory threshold (VT).
DESIGN: Cross-sectional and longitudinal clinical intervention study with exercise education.
SUBJECTS: In total, 30 Japanese overweight men (BMI, 29.0 +/- 2.2 kg/m(2)) and 31 normal- weight men (BMI, 22.5 +/- 1.6 kg/m(2)) at baseline were enrolled: 30 overweight men (BMI, 29.0 +/- 2.2 kg/m(2)) were further enrolled into a 6-month exercise program.
MEASUREMENTS: Fat distribution evaluated by visceral fat ( V) and subcutaneous fat ( S) areas measured with computed tomography scanning at umbilical levels, angiogenic peptides including VEGF and bFGF, exercise tests at baseline and after 6 months.
RESULTS: In normal- weight and overweight subjects at baseline, VEGF positively correlated with S area (r = 0.350, P = 0.007) but not with V area. In contrast, bFGF negatively correlated with BMI (r = - 0.619, P<0.001), S (r = - 0.457, P<0.001) and V areas (r = -0.466, P<0.001). By intervention with exercise education, 30 overweight subjects showed reduction in BMI (29.0 +/- 2.2 to 28.0 +/- 2.0, P<0.001), V and S areas, increase in VO2 and WR at VT, increase in bFGF (9.21 +/- 5.82 - 21.2+/-7.04 ng/ ml, P<0.001), and no change in VEGF (1.45 +/- 0.72 - 1.88 +/- 0.52 ng/ml, P = 0.016). The stepwise multiple regression analysis revealed that &UDelta;BMI (β = - 6.052) and &UDelta;VO2 (β = 2.806) were independently related to &UDelta;bFGF (P<0.001) and all other variables including DeltaS area, and DeltaV area, and DeltaWR did not enter the equation at significant levels.
CONCLUSION: The present study indicated a negative correlation between serum bFGF levels and BMI at baseline as well as an association of DeltaBMI and DeltaVO(2) with DeltabFGF after exercise intervention. The exercise-induced elevation of bFGF may be beneficial in the prevention of the atherosclerosis in overweight subjects.

DOI： 10.1038/sj.ijo.0802408

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