Faculty Profiles - WADA Jun

Papers - WADA Jun

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Relevance of renal-specific oxidoreductase in tubulogenesis during mammalian nephron development Reviewed

YS Kanwar, QW Yang, YF Tian, S Lin, J Wada, S Chugh, SK Srivastava

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 282 ( 4 ) F752 - F762 2002.4

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

Renal-specific oxidoreductase (RSOR), an enzyme relevant to diabetic nephropathy, is exclusively expressed in renal tubules. Studies were initiated to determine whether, like other tubule-specific proteins, it selectively modulates tubulogenesis. Northern blot analyses revealed a similar to1.5-kb transcript, and RSOR expression was detectable in mice embryonic kidneys at day 13, gradually increased by day 17, and extended into neo- and postnatal periods. RSOR mRNA and protein expression was confined to proximal tubules, commencing at gestational day 17 and increasing subsequently, but remained absent in glomeruli and medulla. Treatment with RSOR antisense oligodeoxynucleotide resulted in a dose-dependent dysmorphogenesis of metanephric explants harvested at gestational day 13. The explants were smaller and had expanded mesenchyme, and the population of tubules was markedly decreased. The glomeruli were unaffected, as assessed by mRNA expression of glomerular epithelial protein 1 and reactivity with wheat germ agglutinin. Antisense treatment led to a selective reduction of RSOR mRNA. Immunoprecipitation also indicated a selective translational blockade of RSOR. These findings suggest that RSOR is developmentally regulated, exhibits a distinct spatiotemporal distribution, and probably plays a role in tubulogenesis.

DOI： 10.1152/ajprenal.00181.2001

Relationship between reduced serum IGF-I levels and accumulation of visceral fat in Japanese men Reviewed

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

INTERNATIONAL JOURNAL OF OBESITY 26 ( 3 ) 361 - 369 2002.3

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

OBJECTIVE: To investigate whether the changes in IGF-1 concentrations after weight reduction in Japanese overweight men are associated with changes in visceral and subcutaneous fat.
DESIGN: Cross-sectional and longitudinal clinical intervention study with exercise education.
SUBJECTS: One-hundred and twelve Japanese overweight men aged 30-59y (body mass index (BMI) 28.4+/-2.5 kg/m(2)) and 33 normal-weight men aged 30-39y (BMI 22.1+/-1.5 kg/m(2)) at baseline. From the participants, 56 randomly selected overweight men (BMI 28.8+/-2.8) were further enrolled into a 1 y exercise program.
MEASUREMENTS: Fat distribution was evaluated by visceral fat M and subcutaneous fat (S) areas measured with computed tomography scanning at umbilical levels, metabolic parameters and hormones including insulin, leptin and IGF-1 at baseline and after 1 y.
RESULTS: In 112 overweight subjects at baseline, insulin (10.5+/-5.0 muUl/ml) and leptin (6.4+/-3.7 ng/ml) significantly correlated with both V (r=0.260, P=0.0073; r=0.410, P<0.0001) and S areas (r=0.377, P<0.0001; r=0.613, P<0.0001), respectively. IGF-1 (156.8+/-48.7 muU/ml) significantly and negatively correlated with V area (r= -0.242, P=0.0125)and age (r= - 0.192, P=0.0480). In normal-weight men aged 30-39y (n=33) and age-matched subjects (n=30) selected from the 112 overweight men, the serum IGF-1 further tightly correlated with V area (r= - 0.467, P<0.0001). Visceral fat area and age were independently related to serum IGF-1 levels by multiple regression analysis. By intervention with exercise education, 56 overweight subjects showed an increase in daily steps (6224+/-2781 to 7898+/-4141 steps/day) and reduction of BMI (28.8+/-2.8 to 27.7+/-2.9). DeltaIGF-1 significantly correlated with DeltaV area (r= - 0.432, P = 0.0009) but not with DeltaS area or DeltaBMI.
CONCLUSION: The present study indicated a negative correlation between IGF-1 levels and visceral fat at baseline as well as an association between the reduction in visceral fat and increase in IGF-1 levels after an exercise intervention.

DOI： 10.1038/sj/ijo/0801899

Angiocentric immunoproliferative lesions of the lung associated with diffuse renal involvement Reviewed

S Okada, J Wada, T Tsukinoki, N Hirano, Y Watanabe, K Shikata, Y Yamasaki, S Takase, T Yoshino, T Akagi, H Makino

AMERICAN JOURNAL OF KIDNEY DISEASES 39 ( 3 ) 2002.3

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

A 62-year-old Japanese man presented with high fever, cough, and sputa. Computed tomography (CT) scan of the chest revealed lung infiltrates with air bronchogram of the right middle lobe and mediastinal lymphadenopathy. Bronchoscopic examination was performed, and Mycobacterium avium complex was detected from bronchoalveolar lavage fluid. Although the administration of clarithromycin and levofloxacin improved the patient's symptoms, the lung infiltrates on chest CT scan gradually worsened. Lung biopsy of segments 4 and 8 by video-assisted thorachoscopy revealed angiocentric and angiodestructive massive lymphoplasmocytic Infiltrations with multinucleated giant cells, which were compatible with grade II angiocentric immunoproliferative lesions. The patient was found to have deterioration of renal function, and glomerular filtration rate was 32.6 mL/min. His kidneys were enlarged and showed prominent and diffuse uptake of gallium-67 citrate. Percutaneous renal biopsy revealed massive infiltration of CD4(+) mononuclear cells, plasma cells, and eosinophils in the interstitium and destruction of normal structure of tubules. Blood vessels were destroyed and replaced by inflammatory cells. The combination chemotherapy achieved a remission, and the patient has remained free of disease at 2 years after onset of the illness. We recommend the imaging of kidneys for diagnosis and following renal biopsy to evaluate the renal involvement of angiocentric immunoproliferative lesions. (C) 2002 by the National Kidney Foundation, Inc.

DOI： 10.1053/ajkd.2002.31423

Cyanotic congenital heart disease associated with glomerulomegaly and focal segmental glomerulosclerosis: Remission of nephrotic syndrome with angiotensin converting enzyme inhibitor Reviewed

K Hida, J Wada, H Yamasaki, Y Nagake, H Zhang, H Sugiyama, K Shikata, H Makino

NEPHROLOGY DIALYSIS TRANSPLANTATION 17 ( 1 ) 144 - 147 2002.1

Gene expression and identification of gene therapy targets in diabetic nephropathy Reviewed

Jun Wada, Hirofumiand Makino, Yashpal S. Kanwar

Kidney International 61 ( 1 ) S73 - S78 2002

Language：English Publishing type：Research paper (international conference proceedings) Publisher：Blackwell Publishing Inc.

A number of novel genes that are upregulated in diabetic kidneys have been identified. Recently, transforming growth factor-β (TGF-β)-driven secreted proreins, i.e., connective tissue growth factor (CTGF) and gremlin, were identified. They are up-regulated in kidneys of diabetic animals and modulate the biology of mesangial cells. CTGF mediates TGF-β-induced matrix overproduction by the mesangial cells. Gremlin is a putative antagonist of bone morphogenetic protein-2 that blocks mesangial cell proliferation. Thus, gremlin may modulate the biology of mesangium by stimulating mesangial cell proliferation and in turn production of matrix. In addition, transcriptionally regulated kinases, serum glucocorticoid-regulated kinase and munc-13 have been identified. The former stimulates renal tubular Na+ transport and is involved in hyperfiltraion of diabetic kidneys by a Na+ transport feedback mechanism. Munc-13 has been shown to induce apoptosis in hyperglycemic state via diacylglyecrol-activated, PKC-independent signaling pathway. Another pathway relevant to diabetic nephropathy is polyol pathway, where glucose is reduced to sorbitol by aldose reductase. Recently, a renal-specific reductase of the aldo-keto reductase family was isolated. It is up-regulated in diabetic mice, and this could serve as a suitable target for gene therapy in renal complications of diabetes. Several mitochondrial genome-encoded genes, such as, cytochrome oxidase and NADH dehydrogenase, are up-regulated in diabetic kidneys. A novel nuclear-encoded mitochondrial gene, i.e., translocase inner mitochondrial membrane 44 (Tim44), is up-regulated in diabetic kidneys, and it may also serve as another target for molecular therapeutic intervention at the core storage energy sites, i.e., mitochondria. In this review, these novel differentially regulated genes that respond to hyperglycemic stress are described, and they may serve as possible targets for gene therapy in the treatment of diabetic nephropathy.

DOI： 10.1046/j.1523-1755.2002.0610s1073.x

Relevance of extracellular matrix and its receptors in mammalian nephrogenesis revealed by metanephric organ culture system Reviewed

J Wada, YS Kanwar, H Makino

NEPHROLOGY DIALYSIS TRANSPLANTATION 17 75 - 77 2002

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

Mammalian nephrogenesis is modulated by a number of extracellular matrix (ECM) glycoproteins, integrins and cell adhesion molecules. We demonstrated the existence of integrins alphavbeta1, alphavbeta3, alphavbeta5 and alphavbeta6 in epithelial elements of developing nephrons. Fibrillin-1 is a putative ligand for integrin alphavbeta3, and tubulo-interstitial nephritis antigen (TIN-ag) is a ligand for integrins alphavbeta3 and alpha3beta1. Fibrillin-1 and TIN-ag are also differentially expressed in the developing kidney. The inclusion of antisense oligonucleotide in a mouse kidney organ culture system indicated that the alphav-related integrins and their ligands play an important role in mammalian nephrogenesis. Recently identified modulators of cell-matrix interactions, i.e. beta-galactoside-binding mammalian lectins (galectins), are involved in cell-cell and cell-matrix interactions by cross-linking glycoconjugates located on the ECM and membrane-bound glycoproteins. We identified and cloned a new member of the galectins from embryonic kidneys, and designated it galectin-9. Since high glucose alters the expression of ECM proteins and integrins, we also investigated the influence of glucose on metanephric development. The presence of 30 mM D-glucose in metanephric organ Culture induced dysmorphogenesis of the kidney accompanied by decreased expression of perlecan. Furthermore, we screened the genes differentially expressed under high glucose conditions in streptozotocin-induced newborn mouse kidneys by representational difference analysis of cDNA. We identified translocase of inner mitochondrial membrane (Tim44) and renal-specific oxido-reductase (RSOR). The roles of these molecules in glucose-induced dysmorphogenesis and the relationship with ECM-related molecules need to be addressed.

Renal gene expression in embryonic and newborn diabetic mice Reviewed

EI Wallner, J Wada, S Lin, XM Pan, JK Reddy, SS Chugh, YS Kanwar

EXPERIMENTAL NEPHROLOGY 10 ( 2 ) 130 - 138 2002

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

Several novel genes that are upregulated in diabetic kidneys have been identified. Recently, transforming growth factor beta driven secreted proteins, i.e., connective tissue growth factor and gremlin (bone morphogenetic protein 2), have been identified, and their expression has been correlated with the tissue changes seen in diabetic nephropathy in the adult population. However, there are very few studies reported in the literature that describe the gene expression in the diabetic state during embryonic and neonatal life. It is well known that exposure to glucose or its epimer, i.e., mannose, induces marked dysmorphogenesis of the embryonic metanephros in an organ culture system. These changes are associated with ATP depletion and marked apoptosis, suggesting an oxidant stress in the induction of dysmorphogenesis of the embryonic metanephros. In view of the glucose-induced changes in the fetal metanephros, a diabetic state was induced by the administration of streptozotocin ouring pregnancy, and newborn mouse kidneys were processed for suppression subtractive hybridization-PCR. In addition, a diabetic state was induced in newborn diabetic mice, and after 1 week their kidneys were harvested and subjected to representational difference analysais of cDNA. Four novel genes with upregulated mRNA expression were identified, They included: (1) a translocase inner mitochondrial membrane 44 that is involved in the ATP-dependent import of preproteins from the cytosol into the mitochondrial matrix; (2) a kidney-specific aldo-keto reductase that utilizes NADPH and NADH as cofactors in the reduction of aromatic aldehydes and aldohexoses; (3) Rap1b, a Ras-related small GTP-binding protein that behaves as a GTPase and cycles between GTP-bound (active) and GDP-bound (inactive) states associated with conformational change, and (4) a fusion protein of ubiquitin polypeptide and ribosomal protein L40 (UbA(52) or ubiquitin/60) that is intimately involved in the ubiquitin-dependent proteasome pathway related to the accelerated degradation of proteins under various stress conditions, such as those seen in patients with cancer and diabetes mellitus. Copyright (C) 2002 S. Karger AG, Basel.

Identification of developmentally regulated mesodermal-specific transcript in mouse embryonic metanephros Reviewed

Yashpal S. Kanwar, Anil Kumar, Kosuke Ota, Sun Lin, Jun Wada, Sumant Chugh, Elisabeth I. Wallner

American Journal of Physiology - Renal Physiology 282 ( 5 ) F953 - F965 2002

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

Mesodermal-specific cDNA or transcript (MEST) was identified by suppression subtractive hybridization-PCR of cDNA isolated from embryonic day 13 vs. newborn mice kidneys. At day 13 of mouse gestation, a high expression of MEST, with a single ∼2.7-kb transcript that was exclusively localized to the metanephric mesenchyme was observed. The MEST mRNA expression gradually decreased during the later stages and then abruptly decreased in the newborn kidneys and subsequent postnatal life, after which a very mild expression persisted in the glomerular mesangium. Regression in mRNA expression during embryonic renal development appears to be related to methylation of the MEST gene. Treatment of metanephroi, harvested at day 13 of gestation with MEST-specific antisense oligodeoxynucleotide resulted in a dose-dependent decrease in the size of the explants and the nephron population. This was associated with a selective decrease in MEST mRNA expression and accelerated apoptosis of the mesenchyme. These findings suggest that MEST, a gene with a putative mesenchymal cell-derived protein, conceivably plays a role in mammalian metanephric development.

Relevance of renal-specific oxidoreductase in tubulogenesis during mammalian nephron development Reviewed

Yashpal S. Kanwar, Qiwei Yang, Yufeng Tian, Sun Lin, Jun Wada, Sumant Chugh, Satish K. Srivastava

American Journal of Physiology - Renal Physiology 282 ( 4 ) F752 - F762 2002

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

Renal-specific oxidoreductase (RSOR), an enzyme relevant to diabetic nephropathy, is exclusively expressed in renal tubules. Studies were initiated to determine whether, like other tubule-specific proteins, it selectively modulates tubulogenesis. Northern blot analyses revealed a ∼1.5-kb transcript, and RSOR expression was detectable in mice embryonic kidneys at day 13, gradually increased by day 17, and extended into neo- and postnatal periods. RSOR mRNA and protein expression was confined to proximal tubules, commencing at gestational day 17 and increasing subsequently, but remained absent in glomeruli and medulla. Treatment with RSOR antisense oligodeoxynucleotide resulted in a dose-dependent dysmorphogenesis of metanephric explants harvested at gestational day 13. The explants were smaller and had expanded mesenchyme, and the population of tubules was markedly decreased. The glomeruli were unaffected, as assessed by mRNA expression of glomerular epithelial protein 1 and reactivity with wheat germ agglutinin. Antisense treatment led to a selective reduction of RSOR mRNA. Immunoprecipitation also indicated a selective translational blockade of RSOR. These findings suggest that RSOR is developmentally regulated, exhibits a distinct spatiotemporal distribution, and probably plays a role in tubulogenesis.

History of nephrology in the past 100 years: Collagen disease and vasculitis

Makino, H., Wada, J.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 91 ( 5 ) 2002

Angiocentric immunoproliferative lesions of the lung associated with diffuse renal involvement.

Okada, S., Wada, J., Tsukinoki, T., Hirano, N., Watanabe, Y., Shikata, K., Yamasaki, Y., Takase, S., Yoshino, T., Akagi, T., Makino, H.

American journal of kidney diseases : the official journal of the National Kidney Foundation 39 ( 3 ) 2002

Management of diabetic nephropathy with nephrotic syndrome

Eguchi, J., Wada, J., Makino, H.

Nippon rinsho. Japanese journal of clinical medicine 60 Suppl 10 2002

Makino, H., Wada, J.

Nippon rinsho. Japanese journal of clinical medicine 60 Suppl 8 2002

Identification of up-regulated Ras-like GTPase, Rap1b, by suppression subtractive hybridization Reviewed

S Lin, S Chugh, XM Pan, EI Wallner, J Wada, YS Kanwar

KIDNEY INTERNATIONAL 60 ( 6 ) 2129 - 2141 2001.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. Diabetic nephropathy accounts for over 30% of the end-stage renal disease (ESRD). A number of defined mechanisms and molecules that are involved in its pathogenesis are known, while others remain to be identified.
Methods. Suppression subtraction hybridization (SSH)-polymerase chain reaction (PCR) was employed to search for new genes that may be relevant to the pathogenesis of diabetic nephropathy during embryonic development, the time when the kidney is most susceptible to various forms of stress. A diabetic state was induced in pregnant mice at day-13 of gestation by administration of streptozotocin. The kidneys of newborn mice with blood glucose level > 200 mg/dL were harvested, mRNA isolated and subjected to SSH-PCR. Several differentially expressed cDNA fragments with up-regulated expression were isolated. One of the cDNA fragments had homology with human Ras-like guanine 5'-triphosphate (GTPase), Rap1b gene. By utilizing the lambda ZAP II mouse cDNA library and SMART (TM) RACE amplification, a full-length Rap1b cDNA was isolated. A recombinant protein was generated in pET15b bacterial expression system. An anti-Rap1b antibody was raised in rabbits by immunizing them with the fusion protein, and its specificity was confirmed by Western blot analysis.
Results. Rap1b cDNA had an open reading frame of 552 by with a predicted putative protein size of similar to 21 kD. In vitro translation verified the authentication of the Rap1b cDNA clone. Northern blot analyses revealed a single similar to2.3 kb Rap1b mRNA transcript. Its expression was up-regulated in several tissues, including the kidney of newborn diabetic mice. The degree of up-regulation of Rap1b mRNA expression was proportional to the blood glucose levels. Western blot analyses confirmed the hyperglycemia-induced up-regulation of the Rap1b expression. In situ hybridization and immunofluorescence studies revealed that Rap1b was expressed in the inner medullary collecting tubules. During hyperglycemia, its expression was accentuated and extended into the outer medullary and cortical collecting tubules. Similar up-regulation of Rap1b was observed when embryonic kidneys, harvested at day-13 of gestation, were exposed to high glucose ambience.
Conclusion. The data suggest that Rap1b, a GTP-binding protein that plays a critical role in various signaling intracellular events, is another molecule that may be relevant to the pathobiology of diabetic nephropathy.

DOI： 10.1046/j.1523-1755.2001.00061.x

Nitric oxide system is involved in glomerular hyperfiltration in Japanese normo- and micro-albuminuric patients with type 2 diabetes Reviewed

K Hiragushi, H Sugimoto, K Shikata, T Yamashita, N Miyatake, Y Shikata, J Wada, Kumagai, I, M Fukushima, H Makino

DIABETES RESEARCH AND CLINICAL PRACTICE 53 ( 3 ) 149 - 159 2001.9

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

Glomerular hyperfiltration plays a pathogenic role in the early stages of diabetic nephropathy. Experimental studies in laboratory animals suggest that nitric oxide (NO) alight be involved in the pathogenesis of glomerular hyperfiltration. We performed a cross-sectional study to determine the relationship between diabetic glomerular hyperfiltration and the NO system. Normoalbuminuric (n=41), microalbuminuric (n=25), and macroalbuminuric(n=16) patients with type 2 diabetes were recruited in this study and compared with age-matched 84 non-diabetic control subjects. Creatinine clearance and urinary NO2-/NO3- excretion (urinary NOx) were measured, and the expression of endothelial cell nitric oxide synthase (ecNOS) was evaluated in human renal tissues. Glomerular hyperfiltration was present in 19 (37.5%) and nine (36.6%) of normoalbuminuric and microalbuminuric type 2 diabetic patients, respectively. The urinary NOx was significantly higher in normoalbuminuric patients compared with normal subjects. Creatinine clearance correlated significantly with urinary NOx in normoalbuminuric and micro albuminuric patients. Immunohistochemical staining intensities for ecNOS were significantly increased in glomerular endothelial cells of microalbuminuric type 2 diabetic patients as compared with the control subjects. These results suggest that NO may contribute to the: pathogenesis of glomerular hyperfiltration in Japanese type 2 diabetic patients. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0168-8227(01)00260-1

Ultrastructure of glomerular basement membrane in active Heymann nephritis rats revealed by tissue-negative staining method Reviewed

Y Hayashi, K Hironaka, K Shikata, S Ogawa, K Ota, J Wada, K Kamata, Z Ota, H Makino

AMERICAN JOURNAL OF NEPHROLOGY 21 ( 3 ) 249 - 255 2001.5

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

Recently, we have developed a tissue-negative staining method, and successfully visualized fine meshwork structure of the glomerular basement membrane (GBM). To clarify the mechanism of proteinuria in active Heymann nephritis, we performed tissue-negative staining and investigated the ultrastructural alterations of the GEM. Active Heymann nephritis, the animal model of human membranous nephropathy, was induced in Lewis rats by the injection of proximal tubular brush border antigen, i.e. Fx1A. Urinary protein excretion was measured and histological studies were performed over 15 weeks following the Fx1A injection. Proteinuria developed at 10 weeks after injection (38.2 +/-7.4 mg/day) and progressively increased (160.2 +/- 20.6 mg/day at 15 weeks). Capillary fine deposits of IgG and C3 were seen by immunofluorescence, and subepithelial electron dense deposits (EDD) by transmission electron microscopy (TEM). Using the tissue-negative staining method, regular meshwork structure consisted of fine fibrils and pores (2.5 +/- 0.7 nm in short dimension) was observed in the GEM of control rats. At 10 and 15 weeks after injection, the GEM, directly facing the endothelial side of EDD, contained enlarged pores and nephrotic tunnels. Mean values of the short dimension of enlarged pores were 2.9 +/- 0.5 nm at 10 weeks and 3.1 +/-0.4 nm at 15 weeks, which were significantly larger than that of control rats (p < 0.01). The rest area of the GEM, including newly produced GEM covering the epithelial side of EDD, had no significant difference in size of the pores from control GEM and no tunnels. Although there was no significant difference in the size of enlarged pores between 10 and 15 weeks, the percentage area of GBM with impaired size barrier increased at 15 weeks (51.4<plus/minus>8.1%) compared with 10 weeks (24.0 +/-8.3%) and related to severity of proteinuria. The density of the tunnels also increased at 15 weeks. In conclusion, immune deposits may affect the GBM biosynthesis and induce the defect of size barrier of the GEM, which is responsible for proteinuria in active Heymann nephritis. Copyright (C) 2001 S. Karger AG, Basel.

DOI： 10.1159/000046257

Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys Reviewed

H Zhang, J Wada, K Hida, Y Tsuchiyama, K Hiragushi, K Shikata, HY Wang, S Lin, YS Kanwar, H Makino

JOURNAL OF BIOLOGICAL CHEMISTRY 276 ( 20 ) 17132 - 17139 2001.5

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

Collectrin, a novel homolog of angiotensin-converting enzyme-related carboxypeptidase (ACE2), was identified during polymerase chain reaction-based cDNA subtraction and up-regulated in 5/6 ablated kidneys at hypertrophic phase. Collectrin, with 222 amino acids, has an apparent signal peptide and a transmembrane domain; the sequence is conserved in mouse, rat, and human and shares 81.9% identity. Human collectrin has 47.8% identity with non-catalytic extracellular, transmembrane, and cytosolic domains of AGES; however, unlike ACE and AGES, collectrin lacks active dipeptidyl carboxypeptidase catalytic domains. The collectrin mRNA transcripts are expressed exclusively in the kidney. In situ hybridization reveals its mRNA expression in renal collecting ducts, and immunohistochemistry shows that it is localized to the luminal surface and cytoplasm of collecting ducts. Immunoprecipitation studies, using [S-35]methionine-labeled renal cortical and inner medullar collecting duct cells, i.e. M-1 and mIMCD-3, indicate that the protein size is similar to 32 kDa. During the development of mouse kidney, mRNA signal is detectable at day 13 of gestation, and the protein product is observed in the ureteric bud branches. Its expression is progressively increased during later stages of the gestation extending into the neonatal periods and then is decreased in adult life. Up-regulated expression of collectrin in the hypertrophic kidneys after renal ablation and restricted spatio-temporal expression during development indicates a possible role(s) in the process of progressive renal failure and renal organogenesis.

DOI： 10.1074/jbc.M006723200

Gene expression profile in streptozotocin-induced diabetic mice kidneys undergoing glomerulosclerosis Reviewed

J Wada, H Zhang, Y Tsuchiyama, K Hiragushi, K Hida, K Shikata, YS Kanwar, H Makino

KIDNEY INTERNATIONAL 59 ( 4 ) 1363 - 1373 2001.4

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

Background. To elucidate the molecular mechanism of diabetic nephropathy, a high-density DNA filter array was employed to survey the gene expression profile of streptozotocin-induced diabetic CD-1 (ICR) mouse kidneys.
Methods. Ten-week-old CD-1 male mice were divided into four groups: (1) control, (2) unilaterally nephrectomized (UX) mice, (3) streptozotocin (STZ)-induced diabetic (STZ) mice, and (4) STZ mice with unilateral renal ablation (STZ-UX). Pathological changes were examined at 24 weeks after the induction. The gene expression profile was compared between the control and STZ mice by a Gene Discovery Array (GDA).
Results. The glomeruli in UX mouse kidney showed prominent glomerular hypertrophy, while the accumulation of mesangial matrix was minimal. Both STZ and STZ + UX mice had significant glomerular hypertrophy and glomerulosclerosis, and the lesions were not enhanced by renal ablation. By comparison between control and STZ mice, 16 clones that increased in expression with the induction of diabetes and 65 clones that decreased in diabetic kidneys were identified. The 37 known genes were related to glucose and lipid metabolism, ion transport, transcription factors, signaling molecules, and extracellular matrix-related molecules. The genes known to be involved in cell differentiation and organogenesis in various tissues (that is, Unc-18 homolog, POU domain transcription factor 2, lunatic fringe gene homolog, fibrous sheath component 1, Sox-17, fibulin 2, and MRJ) were found to be differentially expressed in the early phase of diabetic kidneys.
Conclusions. Hyperglycemia is a major determinant of glomerulosclerosis in STZ-induced diabetic CD-1 mice, and the altered gene expression in the early phase of diabetic kidney may be critical for the development of diabetic nephropathy.

DOI： 10.1046/j.1523-1755.2001.0590041363.x

Galectins, galactoside-binding mammalian lectins: Clinical application of multi-functional proteins Reviewed

J Wada, H Makino

ACTA MEDICA OKAYAMA 55 ( 1 ) 11 - 17 2001.2

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Galectins are beta -galactoside binding mammalian lectins and they share homologous carbohydrate recognition domains. To date, 11 members of galectin family have been cloned and identified. They have been shown to play roles in diverse biological events, such as embryogenesis, oncogenesis, adhesion and proliferation of the cells, receptor for advanced glycation end products, mRNA splicing, bacterial colonization, apoptosis, and in the modulation of the immune response, The mechanisms by which galectins exert these diverse effects remain largely unknown. However, the elucidation of multi-functional proteins belong fro galectin family are going to open new fields in clinical science including diagnosis and therapy of autoimmune disorders, cancers, and vascular complications in diabetes and hypertension.

DOI： 10.18926/AMO/32029

Status of glucose transporters in the mammalian kidney and renal development Reviewed

EI Wallner, J Wada, G Tramonti, S Lin, YS Kanwar

RENAL FAILURE 23 ( 3-4 ) 301 - 310 2001

Language：English Publishing type：Research paper (scientific journal) Publisher：MARCEL DEKKER INC

Glucose is the main source of energy for the mammalian cells and its entry is mediated via various transporters. About 7 facilitative (GULT-1 to -7) and 2 concentrative glucose transporters (SGLT-1 and -2) have been identified: The facilitative glucose transporters allow the glucose entry into the cell interior due to the concentration gradient and the latter via the Nam-dependent electrochemical gradient. They have similar structural motifs with 12-14 putative transmembrane domains with a predicted protein size varying from 50 to 76 kDa. Some of the facilitative glucose transporters (GLUT-1, -2, -4 and -5) and both the sodium glucose co-transporters (SGLT-1 and -2) are expressed in the kidney. The transporters that are involved in the major transport of glucose in the kidney include GLUT-2 and SGLT-2. They are of high capacity and low affinity type and are expressed in the SI segment of the proximal tubule. All the transporters expressed in the kidney are developmentally regulated. The mRNA expression of renal GLUTS is variable during the fetal and postnatal periods. On the other hand the mRNA of SGLTs increases steadily from the fetal period to maturity along with the increase in their functional activity, i.e,, glucose uptake. Recent studies indicate that the SGLTs are believed to selectively regulate tubulogenesis since they are expressed in the metanephric tubules very early in the embryonic life in mammals.

DOI： 10.1081/JDI-100104714

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