Faculty Profiles - KAWACHI Hiroshi

Papers - KAWACHI Hiroshi

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Continuous, noninvasive monitoring of local microscopic inflammation using a genetically engineered cell-based biosensor Reviewed

YM Meng, A Kasai, N Hiramatsu, K Hayakawa, K Yamauchi, M Takeda, H Kawachi, F Shimizu, J Yao, M Kitamura

LABORATORY INVESTIGATION 85 ( 11 ) 1429 - 1439 2005.11

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

Using an inflammation-responsive regulatory element as a molecular sensor, we established a cell-based biosensor for continuous, noninvasive monitoring of local microscopic inflammation in vivo. Glomerular mesangial cells were stably transfected with a marker gene encoding secreted alkaline phosphatase (SEAP) under the control of the kappa B enhancer elements. The established cells secreted SEAP in vitro in response to proinflammatory cytokines as well as to soluble factors produced by inflamed glomeruli. To examine feasibility of using the established cells for in vivo monitoring of local microscopic inflammation, the sensor cells were transferred selectively into rat glomeruli via the renal circulation. After induction of acute glomerulonephritis, the serum level of SEAP was increased transiently in cell-transferred nephritic rats. The kinetics of serum SEAP was closely correlated with the natural course of the inflammation, and the increase in SEAP was attenuated by suppression of inflammation using an immunosuppressive drug, cyclophosphamide. Neither cell-transferred normal rats nor nephritic rats without cell transfer exhibited increase in the serum level of SEAP. When the sensor cells were transferred extrarenally, elevation of serum SEAP was not observed in nephritic rats, confirming that the locally settled sensor cells responded only to local inflammation. These results suggested that, without invasive procedures like tissue biopsies, continuous monitoring of microscopic inflammation is feasible in vivo via locally created, cell-based biosensors.

DOI： 10.1038/labinvest.3700341

Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome Reviewed

M Koshikawa, M Mukoyama, K Mori, T Suganami, K Sawai, T Yoshioka, T Nagae, H Yokoi, H Kawachi, F Shimizu, A Sugawara, K Nakao

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 16 ( 9 ) 2690 - 2701 2005.9

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

Podocytes play an important role in maintaining normal glomerular function and structure, and podocyte injury leads to proteinuria and glomerulosclerosis. The family of mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase, and p38) may be implicated in the progression of various glomerulopathies, but the role of MAPK in podocyte injury remains elusive. This study examined phosphorylation of p38 MAPK in clinical glomerulopathies with podocyte injury, as well as in rat puromycin aminonucleoside (PAN) nephropathy and mouse adriamycin (ADR) nephropathy. The effect of treatment with FR167653, an inhibitor of p38 MAPK, was also investigated in rodent models. In human podocyte injury diseases, the increased phosphorylation of p38 MAPK was observed at podocytes. In PAN and ADR nephropathy, the phosphorylation of p38 MAPK and ERK was marked but transient, preceding overt proteinuria. Pretreatment with FR167653 (day -2 to day 14, subcutaneously) to PAN or ADR nephropathy completely inhibited p38 MAPK activation and attenuated ERK phosphorylation, with complete suppression of proteinuria. Electron microscopy and immunohistochemistry for nephrin and connexin43 revealed that podocyte injury was markedly ameliorated by FR167653. Furthermore, early treatment with FR167653 effectively prevented glomerulosclerosis and renal dysfunction in the chronic phase of ADR nephropathy. In cultured podocytes, PAN or oxidative stress induced the phosphorylation of p38 MAPK along with actin reorganization, and FR167653 inhibited such changes. These findings indicate that the activation of MAPK is necessary for podocyte injury, suggesting that p38 MAPK and, possibly, ERK should become a potential target for therapeutic intervention in proteinuric glomerulopathies.

DOI： 10.1681/ASN.2004121084

Infusion of angiotensin II reduces loss of glomerular capillary area in the early phase of anti-Thy-1.1 nephritis possibly via regulating angiogenesis-associated factors Reviewed

Yuki Takazawa, Yohei Maeshima, Hiroyuki Kitayama, Yoshihiko Yamamoto, Hiroshi Kawachi, Fujio Shimizu, Hideki Matsui, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino

Kidney International 68 ( 2 ) 704 - 722 2005.8

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

Background. Although angiotensin II (Ang II) is involved in the progression of renal diseases, infusion of Ang II was reported to surprisingly ameliorate the early phase of anti-Thy-1.1 nephritis (Wenzel et al, Kidney Int 61:1020, 2002). Considering the known proangiogenic effect of Ang II and that angiogenic glomerular capillary repair is required for the recovery of damaged glomeruli in rat anti-Thy-1.1 nephritis, we hypothesized that Ang II infusion starting prior to the initiation of nephritis may induce the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), resulting in the increased glomerular capillary area in the early phase. Methods. Ang II was infused (170 ng/min) in rats, and 5 days later, nephritis was induced by the administration of monoclonal 1-22-3 antibodies. Ang II type 1 or type 2 receptor antagonist (AT1R or AT2R, respectively) (losartan or PD123319, respectively) was coadministered. Results. Ang II infusion affected on neither the deposition of Ig nor mesangiolysis in the initial phase, and resulted in the aggravation of creatinine clearance at day 14 and 35 after initiating anti-Thy-1.1 nephritis. Histologic alterations were ameliorated accompanied by reduced loss in rat endothelial cell antigen (RECA)-1(+) endothelial area in Ang II-infused nephritic rats on day 6 and 14 as compared to control nephritic group, and nephritic alterations were mostly resolved on day 35 in both groups. At the early stage (day 6), glomerular expression of VEGF and receptors flk-1 and flt-1 as well as Ang-1, and receptor Tie2 were increased, and glomerular monocyte infiltration and the expression of angiopoietin-2 (Ang-2), a natural antagonist of Ang-1, were reduced. Both Ang II receptors were involved in the regulation of angiogenic factors and receptors. Conclusion. These results demonstrate that infusion of exogenous Ang II starting prior to the induction of nephritis activates VEGF and Ang-1 signaling regulated via both Ang II receptors, potentially leading to the accelerated recovery of injured glomerular endothelial cells in the early phase of anti-Thy-1.1 nephritis. Increased expression of VEGF and Ang-1 on podocytes further suggests the crucial association of endothelial cells and podocytes in maintaining proper glomerular capillary structures. © 2005 by the International Society of Nephrology.

DOI： 10.1111/j.1523-1755.2005.00449.x

Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril Reviewed

Stephanie Krämer, Tanja Loof, Sebastian Martini, Matthias Rückert, Yingrui Wang, Torsten Böhler, Fuijo Shimizu, Hiroshi Kawachi, Hans-H. Neumayer, Harm Peters

American Journal of Physiology - Renal Physiology 289 ( 2 ) F359 - F368 2005.8

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

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg·kg body wt-1·day -1), cGS plus high-dose enalapril (12 mg·kg body wt -1·day-1), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor- β1, fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease. Copyright © 2005 the American Physiological Society.

DOI： 10.1152/ajprenal.00442.2004

Real-time monitoring of mesangial cell-macrophage cross-talk using SEAP in vitro and ex vivo Reviewed

Yiman Meng, Ayumi Kasai, Nobuhiko Hiramatsu, Kunihiro Hayakawa, Masayuki Takeda, Fujio Shimizu, Hiroshi Kawachi, Jian Yao, Masanori Kitamura

Kidney International 68 ( 2 ) 886 - 893 2005.8

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

Background. Macrophage-mesangial cell interaction plays a crucial role in the pathogenesis of glomerulonephritis. We established a novel system for continuous, real-time monitoring of cross-talk between macrophages and mesangial cells in vitro and ex vivo. Methods. Rat mesangial cells were genetically engineered to produce secreted alkaline phosphatase (SEAP) under the control of the nuclear factor-κB (NF-κB) enhancer elements. The established sensor cells were exposed to macrophages or macrophage-derived factors, and the level of SEAP production was evaluated. Results. In vitro, the established cells expressed and secreted SEAP when exposed to activated macrophages or to cytokines produced by macrophages. The kinetics of SEAP activity in culture media was closely correlated with the expression level of SEAP mRNA. The sensor cells also secreted SEAP in response to media conditioned by macrophage-accumulating, inflamed rat glomeruli. When the sensor cells were transferred adoptively into rat glomeruli subjected to acute anti-Thy 1 glomerulonephritis, the isolated glomeruli containing sensor cells secreted SEAP rapidly and progressively. Conclusion. These data suggested that the established system provides simple and useful tools for monitoring of cross-talk between macrophages and mesangial cells in vitro and ex vivo. This approach would be useful for investigation of molecular mechanisms involved in mesangial cell-macrophage interaction and also for screening of therapeutic agents that efficiently interfere with the link between infiltrating leukocytes and resident glomerular cells. © 2005 by the International Society of Nephrology.

DOI： 10.1111/j.1523-1755.2005.00471.x

Stimulation of soluble guanylate cyclase slows progression in anti-thy1-induced chronic glomerulosclerosis Reviewed

YR Wang, S Kramer, T Loof, S Martini, S Kron, H Kawachi, F Shimizu, HH Neumayer, H Peters

KIDNEY INTERNATIONAL 68 ( 1 ) 47 - 61 2005.7

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

Background. A critical role of soluble guanylate cyclase and nitric oxide-dependent cyclic 3',5'-guanosine monophosphate (cGMP) production for glomerular matrix expansion has recently been documented in a rat model of acute anti-thy1 glomerulonephritis. The present study analyzes the renal activity of the nitric oxide-cGMP signaling cascade in and the effect of the specific soluble guanylate cyclase stimulator Bay 41-2272 on a progressive model of anti-thy1-induced chronic glomerulosclerosis.
Methods. Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized rats. One week after disease induction, animals were randomly assigned to chronic glomerulosclerosis, chronic glomerulosclerosis plus Bay 41-2272 (10 mg/kg body weight/day) or chronic glomerulosclerosis plus hydralazine (15 mg/kg body weight/day). In week 16, analysis included effects on systolic blood pressure, proteinuria, kidney function, glomerular and tubulointerstitial matrix protein accumulation, expression of transforming growth factor-beta 1 (TGF-beta 1), fibronectin and plasminogen activator inhibitor type 1 (PAI-1), macrophage infiltration, cell proliferation, basal and nitric oxide-stimulated cGMP production as well as tubulointerstitial mRNA expression of alpha 1 and beta 1 soluble guanylate cyclase.
Results. The moderately elevated systolic blood pressure seen in the chronic glomerulosclerosis group was comparably decreased by both treatments. Compared to normal controls, soluble guanylate cyclase mRNA expression and nitric oxide-stimulated cGMP production were up-regulated in the tubulointerstitium of the untreated chronic glomerulosclerosis animals, while its activity was decreased in glomeruli. Bay 41-2272 treatment enhanced glomerular and tubulointerstitial nitric oxide-cGMP signaling significantly. This went along with markedly reduced glomerular and tubulointerstitial macrophage infiltration, number of proliferating cells, matrix expression and accumulation, as well as improved kidney function. In contrast, hydralazine therapy did not significantly affect renal nitric oxide-cGMP signaling, macrophage number, cell proliferation, matrix protein expression and accumulation.
Conclusion. Glomerular and tubulointerstitial soluble guanylate cyclase activity are discordantly altered in anti-thy1-induced chronic glomerulosclerosis. Stimulation of soluble guanylate cyclase signaling by Bay 41-2272 limits the progressive course of this model toward tubulointerstitial fibrosis and impaired renal function at least in part in a blood pressure-independent manner. The results suggest that soluble guanylate cyclase activation counteracts fibrosis and progression in chronic renal disease.

DOI： 10.1111/j.1523-1755.2005.00380.x

Exploring RNA inteference as a therapeutic strategy for renal disease Reviewed

Y. Takabatake, Y. Isaka, M. Mizui, H. Kawachi, F. Shimizu, T. Ito, M. Hori, E. Imai

Gene Therapy 12 ( 12 ) 965 - 973 2005.6

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

The short synthetic interfering RNA duplexes (siRNAs) can selectively suppress gene expression in somatic mammalian cells without nonselective toxic effects of double-stranded RNA (dsRNA). However, a selective in vivo delivery of siRNA transfer has not been reported in kidney. Here, we investigated whether injection of synthetic siRNAs via renal artery followed by electroporation could be effective and therapeutic in silencing specific gene in glomerulus. We investigated the effect of siRNA in rat cultured mesangial cells (MCs) and showed that siRNA sequence-specific suppression of transgene expression was over a 1000-fold more potent than that by antisense oligodeoxynucleotide (ASODN). Transfection of siRNA targeting luciferase into rat kidneys significantly inhibited expression of a cotransfected luciferase expression vector in vivo. The delivery of siRNA targeting enhanced green fluorescent protein (EGFP) in the transgenic 'green' rat reduced endogenous EGFP expression, mainly in glomerular MCs. Furthermore, RNAi targeting against TGF-β1 significantly suppressed TGF-β1 mRNA and protein expression, thereby ameliorated the progression of matrix expansion in experimental glomerulonephritis. In addition, vector-based RNAi also inhibited TGF-β1 expression in vitro and in vivo. In conclusion, siRNA-directed TGF-β1 silencing may be of therapeutic value in the prevention and treatment of fibrotic diseases. © 2005 Nature Publishing Group. All rights reserved.

DOI： 10.1038/sj.gt.3302480

Expression and regulation of adrenomedullin in renal glomerular podocytes Reviewed

M Hino, M Nagase, S Kaname, S Shibata, T Nagase, S Oba, M Funaki, N Kobayashi, H Kawachi, P Mundel, T Fujita

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 330 ( 1 ) 178 - 185 2005.4

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

Adrenomedullin (AM) is postulated to exert organ-protective effects. It is expressed in the renal glomeruli, but its roles in the glomerular podocytes have been poorly elucidated. In the present study, we investigated the expression and regulation of AM in recently established conditionally immortalized mouse podocyte cell line in vitro and podocyte injury model in vivo. The cultured differentiated podocytes expressed AM mRNA and secreted measurable amount of AM. AM secretion from the podocytes was increased by H2O2, hypoxia, puromycin aminonucleoside (PAN), albumin overload, and TNF-alpha. Real-time RT-PCR analysis revealed that AM mRNA expression in the podocytes was enhanced by PAN and TNF-alpha, both of which were suppressed by mitochondrial antioxidants. Furthermore, AM expression was upregulated in the glomerular podocytes of PAN nephrosis rats. These results indicated that AM expression in the podocytes was upregulated by stimuli or condition relevant to podocyte injury, suggesting its potential role in podocyte pathophysiology. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.02.142

Novel molecules in regulating the barrier function of podocyte Reviewed

Hiroshi Kawachi

Japanese Journal of Nephrology 47 ( 3 ) 231 - 232 2005

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

Several recent studies indicated that slit diaphragm (SD) of glomerular epithelial cell (podocyte) plays a critical role in maintaining the permeability barrier of glomerular capillary wall. It is also reported that common proteinuric diseases such as minimal change type nephrotic syndrome (MCNS) and membranous nephropathy resulted from the dysfunction of SD. Although our group has reported that nephrin and podocin are critical components of SD, the precise molecular composition constituting the barrier of podocyte is not fully elucidated. To search for novel molecules involved in the development of proteinuria, we performed the subtraction hybridization techniques using glomerular cDNA materials from normal rats and the proteinuric rats with podocyte specific injuries. We identified 71 genes down-regulated in puromycin aminonucleoside nephropathy, an experimental model of MCNS. We confirmed that 11 genes of them were specifically expressed in podocyte in glomeruli and their expressions were already decreased before the onset of proteinuria. Decreased expressions of them are also observed in another proteinuric model induced by anti-nephrin antibody. The observations suggested that these molecules are involved in the development of proteinuria. In this symposium, we will introduce the nature of these molecules. © 2005, Japanese Society of Nephrology. All rights reserved.

DOI： 10.14842/jpnjnephrol1959.47.231

Multi-glycoside of Tripterygium wilfordii hook f. ameliorates proteinuria and acute mesangial injury induced by anti-Thy1.1 monoclonal antibody Reviewed

YG Wan, LB Gu, K Suzuki, T Karasawa, Y Fujioka, GD Han, H Koike, H Kawachi, F Shimizu

NEPHRON EXPERIMENTAL NEPHROLOGY 99 ( 4 ) E121 - E129 2005

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

Background/Aims: Multi-glycoside from Tripterygium wilfordii Hook f. (GTW) is used for various immune and inflammatory diseases including renal diseases represented by mesangial proliferative glomerulonephritis (MsPGN) in China. However, there have been no fundamental studies on the operating mechanism of GTW on MsPGN. The aim of this study is to examine as the first step the effects of GTW on acute injurious process such as mesangial injury and proteinuria in an acute and reversible Thy. 1.1 glomerulonephritis (Thy1.1GN) model and then to clarify the action mechanism of GTW at molecular level by examining its effects on various injurious factors in this model. Methods: Thy1.1 GN was induced in rats by a single intravenous injection with 500 mu g of anti-Thy1.1 mAb 1-22-3. Daily oral administration of GTW and vehicle as a control was started from 3 days before injection of mAb to the day of sacrifice in each experiment. Fourteen rats were randomly divided into 2 groups, GTW-treated and vehicle-treated groups, and sacrificed on day 14 in experiment 1 or on day 7 in experiment 2 after induction of Thy1.1 GN. Proteinuria was determined on days 1, 3, 5, 7, 10 and 14 in experiment 1 or on 1, 3, 5 and 7 in experiment 2. From blood and kidneys taken at sacrifice, blood biochemical parameters, mesangial morphological changes, glomerular macrophage infiltration, and glomerular mRNA expression of cytokines were examined. Results: In experiment 1, proteinuria and mesangial matrix expansion were significantly attenuated by GTW treatment. In experiment 2, GTW treatment significantly ameliorated proteinuria, mesangial lesions and macrophage accumulation in glomerulus. In addition, it significantly reduced the glomerular expression of mRNA for PDGF, MCP-1 and IL-2. Conclusion: GTW ameliorated not only proteinuria but also mesangial alterations in Thy1.1 GN most likely by reducing expression of injurious cytokines, indicating that GTW has suppressive effects on acute inflammatory changes in glomeruli. Copyright (C) 2005 S. Karger AG, Basel.

DOI： 10.1159/000083980

Nephrin and podocin dissociate at the onset of proteinuria in experimental membranous nephropathy Reviewed

Takeshi Nakatsue, Hiroko Koike, Gi Dong Han, Koichi Suzuki, Naoko Miyauchi, Huaiping Yuan, David J. Salant, Fumitake Gejyo, Fujio Shimizu, Hiroshi Kawachi

Kidney International 67 ( 6 ) 2239 - 2253 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Inc.

Background. The slit diaphragm plays a critical role in maintaining the barrier function of the glomerular capillary wall. The pathogenic mechanism of proteinuria in membranous nephropathy remains uncertain. This study was undertaken to analyze the pathogenic role of slit diaphragm in proteinuria in experimental membranous nephropathy. Methods. The expression and the localization of slit diaphragm-associated molecules (nephrin, podocin, and CD2AP) and other podocyte-associated molecules (podocalyxin and α3 integrin) in passive and active Heymann nephritis were analyzed by immunofluorescence and Western blot analysis. The interaction of slit diaphragm-associated molecules was investigated by the dual-labeling immunofluorescence method. The mRNA expression of these molecules was also analyzed. Results. Shifts in nephrin and podocin staining patterns, from linear to granular, were detected in the early stages of passive Heymann nephritis. These shifts were not parallel, and the dissociation of these molecules was detected by the dual-labeling immunofluorescence method in passive and active Heymann nephritis. Western blot analyses with sequentially solubilized materials indicated that the nephrin-rich fraction changed from being partly detergent-resistant to being predominantly detergent-soluble. This change did not occur with podocin. Nephrin excreted into urine was already detected in the early stages of passive Heymann nephritis. Decreased mRNA expression of nephrin and podocin was observed before the onset of proteinuria. By contrast, no extensive change in the expression of α3 integrin was observed in this study. Conclusion. Nephrin is dissociated from podocin and excreted into urine in the early stages of Heymann nephritis. The reduced expression of nephrin and podocin, along with their dissociation, may contribute to the development of proteinuria in Heymann nephritis. © 2005 by the International Society of Nephrology.

DOI： 10.1111/j.1523-1755.2005.00328.x

Intrarenal injection of bone marrow-derived angiogenic cells reduces endothelial injury and mesangial cell activation in experimental glomerulonephritis Reviewed

Hideki Uchimura, Takeshi Marumo, Osamu Takase, Hiroshi Kawachi, Fujio Shimizu, Matsuhiko Hayashi, Takao Saruta, Keiichi Hishikawa, Toshiro Fujita

Journal of the American Society of Nephrology 16 ( 4 ) 997 - 1004 2005

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

Loss of glomerular endothelial cells has been suggested to contribute to the progression of glomerular injury. Although therapeutic angiogenesis induced by administration of bone marrow-derived endothelial progenitor cells has been observed in disease models of endothelial injury, the effects on renal disease have not been clarified. Whether administration of culture-modified bone marrow mononuclear cells would mitigate the glomerular endothelial injury in anti-Thy1.1 nephritis was investigated. After cultivation under conditions that promote endothelial progenitor cell growth, bone marrow mononuclear cells were labeled with CM-DiI, a fluorescence marker, and injected into the left renal artery of Lewis rats with anti-Thy1.1 glomerulonephritis. The decrease in glomerular endothelial cells was significantly attenuated in the left kidney, as compared with the right, in nephritic rats that received the cell infusion. Glomerular injury score, the area positive for mesangial α-smooth muscle actin, and infiltration of macrophages were significantly decreased in the left kidney. CM-DiI-positive cells were distributed in glomeruli of the left kidney but not in those of the right kidney. Among CM-DiI-labeled cells incorporated into glomeruli, 16.5 ± 1.2% of cells were stained with an endothelial marker, rat endothelial cell antigen-1. Culture-modified mononuclear cells secreted 281.2 ± 85.0 pg of vascular endothelial growth factor per 105 cells per day. In conclusion, intra-arterial administration of culture-modified bone marrow mononuclear cells reduced endothelial injury and mesangial activation in anti-Thy1.1 glomerulonephritis. Incorporation into the glomerular endothelial lining and production of angiogenic factor(s) are likely to contribute to the protective effects of culture-modified mononuclear cells against glomerular injury. Copyright © 2005 by the American Society of Nephrology.

DOI： 10.1681/ASN.2004050367

Suppressive effects of GTW treatment on mesangial lesions in experimental irreversible glomerulosclerosis Reviewed

Yi-Gang Wan, Wei Sun, Fujio Shmizu, Liu-Bao Gu, Koichi Suziki, Tamaki Karasawa, Hiroshi Kawachi

Zhongguo Zhongyao Zazhi 30 ( 5 ) 361 - 365 2005

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

Objective: To examine suppressive effects of multi-glycoside of Tripterygium wilfordii Hook. f. (GTW)on mesangial injury induced by two-injecti on of anti-Thy1. 1 monoclonal antibody (mAb) 1-22-3 in vitro. Method: We established the irreversible model of glomerulosclerosis with anti-Thy1. 1 mAb 1-22-3. After 42 days of oral treatment with GTW (50 mg·kg-1 BW) and vehicle (distilled water), to observe effects of GTW on proteinuria, renal function, mesangial morphological change, and mRNA expressions of collagen type I and TGF-β by light microscope (LM), immunofluorescence (IF), and Reverse Transcription Polymerase Chain Reaction (RT-PCR). Result: GTW ameliorated proteinuria (from day24 to day 42) and mesangial proliferation [total cell number, GTW group 65.67 ± 3.43 vs. control group 87.02 ± 2.41, P &lt
0.05
matrix expansion, GTW group 1.20±0.06 vs. control group 2.77±0.23, P&lt
0.05
α-smooth muscle actin(α-SMA) expression, GTW group 1.75±0.33 vs. control group 2.62±0.15, P&lt
0.05
collagen type I expression, GTW group 1.68±0.31 vs. control group 2.06±0.24, P&lt
0.05], moreover, significantly reduced the glomerular expression of mRNA for collagen type I(53.5% to the control group, P &lt
0.05)and TGF-β(14.7% to the control group, P &lt
0.05)on day 42day. Conclusion: GTW can not only decrease proteinuria, but also ameliorate mesangial alterations probably by the reduction of cytokines. GTW may be a promising agent for the prevention of progressive and irreversible glomerulosclerosis.

Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti-Thy-1 irreversible nephritis Reviewed

Masaki Asai, Toshiaki Monkawa, Takeshi Marumo, Seiichi Fukuda, Mihoko Tsuji, Jun Yoshino, Hiroshi Kawachi, Fujio Shimizu, Matsuhiko Hayashi, Takao Saruta

Hypertension Research 27 ( 12 ) 971 - 978 2004.12

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

Blockade of the renin-angiotensin system has been established as a treatment for heart failure with hypertension and left ventricular hypertrophy, and for progressive kidney diseases. The present study was conducted to examine whether spironolactone, a mineralocorticold receptor antagonist, alone or in combination with cilazapril, an angiotensin converting enzyme (ACE) inhibitor, ameliorates proteinuria and renal lesions in an immune-initiated progressive nephritis model. Wistar rats were uninephrectomized 7 days before injection of anti-Thy-1 monoclonal antibody 1-22-3 to induce progressive glomerulonephritis. The nephritic rats were untreated or treated with spironolactone (400 mg/kg body weight/day), cilazapril (11 mg/kg body weight/day), or both for 10 weeks. Proteinuria was increased in the untreated rats 1 week after nephritis induction and was maintained throughout the experiment. Compared with the untreated animals (212.9± 49.2mg/day), proteinuria was significantly reduced in the spironolactone-treated group (62.0±4.0 mg/day, p=0.0046) and the cilazapril-treated group (71.8±26.0 mg/day, p=0.0048) on day 70 after antibody injection. Further reduction of proteinuria (42.4±4.5 mg/day, p=0.0019 vs. the untreated group) and less renal cortex interstitial fibrotic change (fibrosis score: 142.0±18.4 vs. 80.3±18.5 in the untreated group, p=0.0123) were detected in the spironolactone plus cilazapril-treated group. Blood pressure did not differ among the three treatment groups. In conclusion, spironolactone ameliorates proteinuria to the same degree as cilazapril, and concomitant use of spironolactone and an ACE inhibitor further suppresses renal disease progression. These data suggest that concomitant treatment with spironolactone and an ACE inhibitor has beneficial effects on immune-initiated progressive kidney disease.

DOI： 10.1291/hypres.27.971

ネフローゼ症候群の成因 Invited

河内裕

内科 94 5 - 12 2004.12

蛋白尿の分子機序 Invited

河内裕

日本内科学会誌 93 ( 5 ) 954 - 959 2004.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：日本内科学会

腎糸球体係蹄壁は,内皮細胞,糸球体基底摸,そしてその外側を覆う糸球体上皮細胞足突起の3層からなり,足突起間にはスリット膜とよばれるフィルター様の構造物がある.従来,糸球体係蹄壁の蛋白透過を防ぐメインバリアーは,基底膜であるとする考え方が一般的であったが,近年,上皮細胞スリット膜の重要性を示唆する多くの報告がなされてきている. nephrin, podocinは,スリット膜の機能分子で多くの病態で,蛋白尿発症に関わっていると考えられてきており,今後の治療のターゲットとして有力視されている.

DOI： 10.2169/naika.93.954

Other Link： http://hdl.handle.net/10191/17974

腎炎・ネフローゼ「糸球体から蛋白尿が生じる機序についてお教え下さい」 Invited

河内裕

小児内科 36 241 - 243 2004.12

Src-family kinase Fyn phosphorylates the cytoplasmic domain of nephrin and modulates its interaction with podocin Reviewed

H Li, S Lemay, L Aoudjit, H Kawachi, T Takano

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 15 ( 12 ) 3006 - 3015 2004.12

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

Visceral glomerular epithelial cells (GEC) are critical for normal permselectivity of the kidney. Nephrin is a molecule that is expressed specifically in GEC in a structure called the slit diaphragm and is required for normal morphology and permselectivity of GEC. However, the mechanisms of action of nephrin are not understood precisely. The intracellular domain of nephrin has six conserved tyrosine residues. It was hypothesized that these tyrosine residues are phosphorylated by Src-family kinases and that this phosphorylation modulates the function of nephrin. A transient transfection system was used to study the role of tyrosine phosphorylation of the cytoplasmic domain of nephrin in its function. When nephrin was cotransfected with Src-family kinases Fyn or Src in Cos-1 cells, nephrin was strongly tyrosine phosphorylated by Fyn and less so by Src. The results with tyrosine-to-phenylalanine mutations suggested that multiple tyrosine residues contribute to phosphorylation mediated by Src-family kinases. The intracellular domain of nephrin is known to interact with another slit diaphragm protein, podocin. When nephrin and podocin were transfected with Fyn, the interaction between nephrin and podocin was augmented significantly. Podocin was not tyrosine phosphorylated by Fyn; thus, the increased interaction is likely to be secondary to tyrosine phosphorylation of nephrin. Fyn also significantly augmented the activation of the AP-1 promoter induced by nephrin and podocin. In summary, Fyn phosphorylates the cytoplasmic domain of nephrin on tyrosine, leading to enhanced association with podocin and downstream signaling of nephrin.

DOI： 10.1097/01.ASN.0000146689.88078.80

スリット膜関連の新しい機能分子. Invited

河内裕

日本臨床 62 1823 - 1828 2004.12

Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy Reviewed

T Suganami, M Mukoyama, K Mori, H Yokoi, M Koshikawa, K Sawai, S Hidaka, K Ebihara, T Tanaka, A Sugawara, H Kawachi, C Vinson, Y Ogawa, K Nakao

FASEB JOURNAL 18 ( 13 ) 127 - + 2004.10

Language：English Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

Diabetic nephropathy is the leading cause of end-stage renal disease, for which effective therapy to prevent the progression at advanced stages remains to be established. There is also a long debate whether diabetic glomerular injury is reversible or not. Lipoatrophic diabetes, a syndrome caused by paucity of adipose tissue, is characterized by severe insulin resistance, dyslipidemia, and fatty liver. Here, we show that a genetic model of lipoatrophic diabetes (A-ZIP/F-1 mice) manifests a typical renal injury observed in human diabetic nephropathy that is associated with glomerular hypertrophy, diffuse and pronounced mesangial widening, accumulation of extracellular matrix proteins, podocyte damage, and overt proteinuria. By crossing A-ZIP/F-1 mice with transgenic mice overexpressing an adipocyte-derived hormone leptin, we also reveal that leptin completely prevents the development of hyperglycemia and nephropathy in A-ZIP/F-1 mice. Furthermore, continuous leptin administration to A-ZIP/F-1 mice by minipump beginning at 40 weeks of age significantly alleviates the glomerular injury and proteinuria. These findings demonstrate the therapeutic usefulness of leptin at least for a certain type of diabetic nephropathy. The model presented here will serve as a novel tool to analyze the molecular mechanism underlying not only the progression but also the regression of diabetic nephropathy.

DOI： 10.1096/fj.04-2183fje

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