Faculty Profiles - KAWACHI Hiroshi

Papers - KAWACHI Hiroshi

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蛋白尿の成因最近の進歩. Invited

河内裕

綜合臨床 56 155 - 156 2007.12

Ephrin-B1 localizes at the slit diaphragm of the glomerular podocyte Reviewed

T. Hashimoto, T. Karasawa, A. Saito, N. Miyauchi, G. D. Han, K. Hayasaka, F. Shimizu, H. Kawachi

KIDNEY INTERNATIONAL 72 ( 8 ) 954 - 964 2007.10

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

Ephs and ephrins are a family of membrane-bound proteins that function as receptor-ligand pairs. Members of the Eph-ephrin-B family have recently been reported to regulate the paracellular permeability of epithelial cells. In this study, we analyzed the expression and the function of ephrin-B1 in glomeruli. Using immunofluorescence ( IF), we found that ephrin-B1 was expressed along the glomerular capillary loop. Immunoelectron microscopy revealed that ephrin-B1 expression was restricted at the slit diaphragm. Dual labeled IF showed ephrin-B1 colocalized with the slit diaphragm proteins nephrin and CD2-associated protein. Ephrin-B1 colocalized with nephrin at the late capillary loop stage of kidney development. Additionally, injection of rats with a nephritogenic anti-nephrin antibody ( ANA) reduced ephrin-B1 expression. When podocytes were cultured in vitro, they extruded processes that co-stained for ephrin-B1 and for CD2-associated protein. When these podocytes were treated in culture with small interfering RNA for ephrin-B1, CD2-associated protein was reduced in the processes, with a remaining faint perinuclear staining. We suggest that ephrin-B1 has a role in maintaining barrier function at the slit diaphragm.

DOI： 10.1038/sj.ki.5002454

Prevention of hypertension with or without renin-angiotensin system inhibition precludes nephrin loss in the early stage of experimental diabetes mellitus Reviewed

Roberto Bleuel Amazonas, Rodrigo De Almeida Sanita, Hiroshi Kawachi, José B. Lopes De Faria

Nephron - Physiology 107 ( 2 ) p57 - p64 2007.10

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

Background and Aims: Several lines of clinical evidence support the concept that the reduction of blood pressure may be useful in the prevention of diabetic kidney disease. In young diabetic spontaneously hypertensive rats (SHR), prevention of hypertension reduces several early renal abnormalities including albuminuria. However, the contribution of nephrin loss to albuminuria in this early stage of experimental diabetes is unknown. Therefore, we investigated whether elevation of albuminuria in young diabetic SHR is associated with nephrin loss, and if prevention of hypertension, with or without inhibition of the renin-angiotensin system, precludes these abnormalities. Methods: Diabetes was induced by streptozotocin injection in 4-week-old still normotensive SHR and their genetically normotensive control, Wistar-Kyoto rats. Diabetic SHR were randomized for no treatment, or treatment with captopril, losartan, or triple therapy (hydrochlorothiazide, reserpine and hydralazine) for 20 days. Results: The increase in systolic blood pressure was equally prevented by all treatments. Albuminuria was higher in diabetic SHR and similarly reduced (p &lt
0.05) by captopril, losartan, and triple therapy. Glomerular expression of nephrin was significantly reduced in diabetic SHR in comparison with non-diabetic controls. The antihypertensive treatment prevented the reduction in glomerular expression of nephrin. Conclusions: These results demonstrate that the loss of nephrin is associated with albuminuria in a model of genetic hypertension and diabetes, and that the prevention of development of hypertension restores nephrin and prevents albuminuria. This finding suggests a crucial role of blood pressure in diabetes as determinant of nephrin expression and albuminuria. Copyright © 2007 S. Karger AG.

DOI： 10.1159/000108642

Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression Reviewed

N. Eto, T. Wada, R. Inagi, H. Takano, A. Shimizu, H. Kato, H. Kurihara, H. Kawachi, S. J. Shankland, T. Fujita, M. Nangaku

KIDNEY INTERNATIONAL 72 ( 4 ) 455 - 463 2007.8

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

Podocyte injury is a significant contributor to proteinuria and glomerulosclerosis. Recent studies have shown a renoprotective effect of erythropoietin (EPO) during ischemic kidney disease. In this study, we examine mechanisms by which a long acting recombinant EPO analog, darbepoetin, may confer renoprotection in the puromycin aminonucleoside-induced model of nephrotic syndrome. Darbepoetin decreased the proteinuria of rats treated with puromycin. This protective effect was correlated with the immunohistochemical disappearance of the podocyte injury markers desmin and the immune costimulator molecule B7.1 with the reappearance of nephrin expression in the slit diaphragm. Podocyte foot process retraction and effacement along with actin filament rearrangement, determined by electron microscopy, were all reversed by darbepoetin treatment. The protective effects were confirmed in puromycin-induced nephrotic rats that had been hemodiluted to normal hematocrit levels. Furthermore, puromycin treatment of rat podocytes in culture caused actin cytoskeletal reorganization along with deranged nephrin distribution. All these effects in vitro were reversed by darbepoetin. Our study demonstrates that darbepoetin treatment ameliorates podocyte injury and decreases proteinuria by a direct effect on podocytes. This may be accomplished by maintenance of the actin cytoskeleton and nephrin expression.

DOI： 10.1038/sj.ki.5002311

Tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 potentates the anchorage-independent growth of human hepatoma HepG2 cells

Mariko Hokari, Yasunobu Matsuda, Toshifumi Wakai, Yoshio Shirai, Munehiro Sato, Atsunori Tsuchiya, Masaaki Takamura, Satoshi Yamagiwa, Kenji Suzuki, Shogo Ohkoshi, Takafumi Ichida, Hiroshi Kawachi, Yutaka Aoyagi

LIFE SCIENCES 81 ( 4 ) 336 - 345 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), an adhesion molecule of the immunoglobulin superfamily, has been characterized as a putative tumor suppressor because it is frequently down-regulated in aggressive types of cancer cells. Recently, however, several studies have shown that CEACAM 1 actively contributes to malignant progression or migration in some types of tumor cells, suggesting that the role of CEACAM 1 might be diverse among different types of cancer cells. To investigate the functional consequences of CEACAM 1 expression in hepatocellular carcinoma, we analyzed the status of CEACAM 1 in hepatoma cell lines HLF, PLC/PRF/5, HepG2 and KYN-2. We found that CEACAM1 was only expressed in HepG2 cells, which show a unique property for enhanced anchorage-independent growth. When HepG2 cells were treated with small interfering RNA targeted against CEACAM1, the growth rate in monolayer culture was increased. In contrast, when HepG2 cells were cultured in suspension, inhibition of CEACAM1 expression significantly decreased the growth rate, and the speed of cell-cell attachment was repressed. Hyaluronidase treatment attenuated the growth rate of HepG2 cells in suspension culture, indicating that cell-cell attachment is a requisite for anchorage-independent growth. Our data may reveal the dual role of CEACAM1 on hepatocarcinogenesis, by showing that CEACAM1 acts as a tumor suppressor in HepG2 cells in anchorage-dependent growth conditions, while in anchorage-independent growth conditions, it augments cell proliferation by potentiating the cell-cell attachment. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2007.06.002

Blockade of interferon-gamma-inducible protein-10 attenuates chronic experimental colitis by blocking cellular trafficking and protecting intestinal epithelial cells

Kenji Suzuki, Yusuke Kawauchi, Suresh S. Palaniyandi, Punniyakoti T. Veeraveedu, Masato Fujii, Satoshi Yamagiwa, Hiroyuki Yoneyama, Gi Dong Han, Hiroshi Kawachi, Yoshiaki Okada, Yoichi Ajioka, Kenichi Watanabe, Masamichi Hosono, Hitoshi Asakura, Yutaka Aoyagi, Shosaku Narumi

PATHOLOGY INTERNATIONAL 57 ( 7 ) 413 - 420 2007.7

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

The role of chemokines, especially CXCL10/interferon-gamma-inducible protein 10 kDa (IP-10), a chemokine to attract CXCR3(+) T-helper 1-type CD4(+) T cells, is largely unknown in the pathophysiology of inflammatory bowel disease; ulcerative colitis and Crohn's disease. The authors have earlier shown that IP-10 neutralization protected mice from acute colitis by protecting crypt epithelial cells of the colon. To investigate the therapeutic effect of neutralization of IP-10 on chronic colitis, an anti-IP-10 antibody was injected into mice with newly established murine AIDS (MAIDS) colitis. Anti-IP-10 antibody treatment reduced the number of colon infiltrating cells when compared to those mice given a control antibody. The treatment made the length of the crypt of the colon greater than control antibody. The number of Ki67(+) proliferating epithelial cells was increased by the anti-IP-10 antibody treatment. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)(+) apoptotic cells were observed in the epithelial cells of the luminal tops of crypts in control MAIDS colitis, whereas TUNEL+ apoptotic epithelial cells were rarely observed with anti-IP-10 antibody treatment. In conclusion, blockade of IP-10 attenuated MAIDS colitis through blocking cellular trafficking and protecting intestinal epithelial cells, suggesting that IP-10 plays a key role in the development of inflammatory bowel disease as well as in chronic experimental colitis.

DOI： 10.1111/j.1440-1827.2007.02117.x

Angiotensin II type 1 and type 2 receptors play opposite roles in regulating the barrier function of kidney glomerular capillary wall Reviewed

Koichi Suzuki, Gi Dong Han, Naoko Miyauchi, Taeko Hashimoto, Takeshi Nakatsue, Yumiko Fujioka, Hiroko Koike, Fujio Shimizu, Hiroshi Kawachi

AMERICAN JOURNAL OF PATHOLOGY 170 ( 6 ) 1841 - 1853 2007.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Although angiotensin H (Ang II) type 1 receptor antagonist ameliorates proteinuria, its pharmacological mechanism and the differential roles of Ang H type 1 receptor (AT1R) and type 2 receptor (AT2R) are not well understood. We analyzed the effect of Ang H type 1 receptor antagonist on proteinuria caused by antibody against nephrin, a functional molecule of glomerular slit diaphragm and dysfunction of which is involved in the development of proteinuria in several glomerular diseases. We show here that AT1R antagonist ameliorated proteinuria by preventing a reduction in the functional molecules of the slit diaphragm. We also analyzed the role of AT1R- or AT2R-mediated actions on the expression of the slit diaphragm molecules in an in vivo study of normal rat and in an in vitro study of cultured podocytes. AT1R-mediated action hampered the mRNA expression of the slit diaphragm molecules, whereas AT2R-mediated action enhanced it. These findings indicate that Ang H receptor subtypes play opposite roles in regulating the barrier function of glomerular capillary wall and that the enhancement of AT2R stimulation may serve as a potential therapeutic strategy for proteinuria.

DOI： 10.2353/ajpath.2007.060484

Podocyte as the target for aldosterone - Roles of oxidative stress and Sgk1 Reviewed

Shigeru Shibata, Miki Nagase, Shigetaka Yoshida, Hiroshi Kawachi, Toshiro Fujita

HYPERTENSION 49 ( 2 ) 355 - 364 2007.2

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

Accumulating evidence suggests that mineralocorticoid receptor blockade effectively reduces proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with aldosterone and fed a high-salt diet. Aldosterone induced proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules nephrin and podocin were markedly decreased in aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of aldosterone effector kinase Sgk1. Treatment with eplerenone, a selective aldosterone receptor blocker, almost completely prevented podocyte damage and proteinuria, with normalization of elevated reduced nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition, proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by tempol, a membrane-permeable superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although hydralazine treatment almost normalized blood pressure, it failed to improve proteinuria and podocyte damage. In cultured podocytes with consistent expression of mineralocorticoid receptor, aldosterone stimulated membrane translocation of reduced nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore, aldosterone enhanced the expression of Sgk1, which was inhibited by mineralocorticoid receptor antagonist and tempol. In conclusion, podocytes are injured at the early stage in aldosterone-infused rats, resulting in the occurrence of proteinuria. Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.

DOI： 10.1161/01.HYP.0000255636.11931.a2

SM22 alpha: the novel phenotype marker of injured glomerular epithelial cells in anti-glomerular basement membrane nephritis Reviewed

Asa Ogawa, Minoru Sakatsume, Xingzhi Wang, Yunichi Sakamaki, Yutaka Tsubata, Bassam Alchi, Takeshi Kuroda, Hiroshi Kawachi, Ichiei Narita, Fujio Shimizu, Fumitake Gejyo

NEPHRON EXPERIMENTAL NEPHROLOGY 106 ( 3 ) 77 - 87 2007

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

Background/Aims: Our previous comprehensive analysis of the genes expressed in kidneys with anti-glomerular basement membrane ( GBM) nephritis using DNA microarrays showed that SM22 alpha was one of the highly expressed genes. SM22 alpha is a 22-kDa cytoskeletal protein that is exclusively expressed in smooth muscle cells. We investigated the localization of SM22 alpha at mRNA and protein levels, and its pathological significance in anti-GBM nephritis kidneys. Methods: Northern blot analysis, in situ hybridization, immunohistochemistry and double immunofluorescence studies were performed. The specific antibody ( Ab) against SM22 alpha was obtained by immunization of rabbits with recombinant rat SM22 alpha protein. Results: SM22 alpha mRNA expression was up-regulated in kidneys and inducibly expressed in the parietal and visceral glomerular epithelial cells in anti-GBM nephritis kidneys. Immunohistochemistry with anti-SM22 alpha Ab showed that SM22 alpha protein was localized in the same series of cells. Double immunofluorescence with anti-SM22 alpha and anti- glomerular cell markers demonstrated that SM22 alpha might be expressed in epithelial cells of injured glomeruli. In visceral epithelial cells, SM22 alpha might be expressed in cells in which podocyte specific markers, podocalyxin and nephrin were lost. Conclusion: The injured glomerular epithelial cells in anti-GBM nephritis might undergo structural and functional alterations, including the expression of a smooth muscle marker, SM22 alpha. Copyright (C) 2007 S. Karger AG, Basel.

DOI： 10.1159/000103020

Blockade of IP-10/CXCR3 promotes progressive renal fibrosis Reviewed

Izaya Nakaya, Takashi Wada, Kengo Furuichi, Norihiko Sakai, Kiyoki Kitagawa, Hitoshi Yokoyama, Yuko Ishida, Toshikazu Kondo, Takeshi Sugaya, Hiroshi Kawachi, Fujio Shimizu, Shosaku Narumi, Makoto Haino, Craig Gerard, Kouji Matsushima, Shuichi Kaneko

NEPHRON EXPERIMENTAL NEPHROLOGY 107 ( 1 ) E12 - E21 2007

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

Background/Aim: Fibrosis is a hallmark of progressive organ disease. The 10-kDa interferon-inducible protein IP-10/CXCL10 is a potent chemoattractant for activated T lymphocytes, natural killer cells, and monocytes. However, the involvement of IP-10 in the pathogenesis of renal diseases via its receptor, CXCR3, remains unclear. To contribute to the clarification of this issue was the aim of this study. Methods: The impacts of IP-10 on renal fibrosis were investigated in a unilateral ureteral obstruction model in CXCR3-deficient mice and mice treated with anti-IP-10-neutralizing monoclonal antibody. Anti-IP-10 monoclonal antibody (5 mg/kg/day) was injected intravenously once a day until sacrifice on days 1, 4, or 7 after treatment. The effects of IP-10 were confirmed in cultured tubular epithelial cells. Results: IP-10 and CXCR3 were upregulated in progressive renal fibrosis. Blockade of IP-10/CXCR3 promotes renal fibrosis, as evidenced by increases in interstitial fibrosis and hydroxyproline contents, concomitant decrease in hepatocyte growth factor expression, and converse increase in transforming growth factor-beta 1 in diseased kidneys. IP-10 blockade affected neither macrophage nor T cell infiltration in diseased kidneys. Conclusion: These results suggest that blockade of IP-10 via CXCR3 contributes to renal fibrosis, possibly by upregulation of transforming growth factor-beta 1, concomitant with downregulation of hepatocyte growth factor. Copyright (c) 2007 S. Karger AG, Basel.

DOI： 10.1159/000106505

Histological differences in new-onset IgA nephropathy between children and adults Reviewed

Yohei Ikezumi, Toshiaki Suzuki, Naofumi Imai, Mitsuhiro Ueno, Ichiei Narita, Hiroshi Kawachi, Fujio Shimizu, David J. Nikolic-Paterson, Makoto Uchiyama

NEPHROLOGY DIALYSIS TRANSPLANTATION 21 ( 12 ) 3466 - 3474 2006.12

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

Background. It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN.
Methods. Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry.
Results. Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix.
Conclusions. This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.

DOI： 10.1093/ndt/gfl455

Expression of allograft inflammatory factor-1 in kidneys: A novel molecular component of podocyte Reviewed

Y. Tsubata, M. Sakatsume, A. Ogawa, B. Alchi, Y. Kaneko, T. Kuroda, H. Kawachi, I. Narita, T. Yamamoto, F. Gejyo

KIDNEY INTERNATIONAL 70 ( 11 ) 1948 - 1954 2006.12

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

Our comprehensive gene expression profiles of the kidneys in an anti-glomerular basement membrane (GBM) nephritis model using DNA arrays revealed that allograft inflammatory factor-1 (AIF-1) was one of the highly expressed genes. Here, we explored the pathological significance of AIF-1 expression in the kidneys. The expression pattern of AIF-1 mRNA and protein in the kidneys of normal and diseased rats, such as anti-GBM nephritis and puromycin aminonucleoside nephrosis, was investigated by in situ hybridization, immunohistochemistry, and immunoelectron microscopy. Furthermore, the expression of AIF-1 in human kidneys and urinary sediments was examined. AIF-1 was expressed at both mRNA and protein levels in podocytes of normal and diseased rats, and in infiltrating cells in anti-GBM nephritis kidneys. The expression of AIF-1 in podocytes was constitutive; positive in podocytes of both normal and diseased rats. In humans, AIF-1 was expressed in podocytes and infiltrating inflammatory cells, similarly. Moreover, it was detected in urinary podocytes from patients with immunoglobulin A nephropathy. These data document for the first time that AIF-1, a constitutively expressed protein in rat and human podocytes, is a novel molecular component of podocytes, and that the upregulation of AIF-1 in an anti-GBM nephritis model may mainly be a consequence of its expression in infiltrating cells.

DOI： 10.1038/sj.ki.5001941

蛋白尿発症の分子メカニズム. Invited

河内裕, 鈴木浩一

医学のあゆみ 216 680 - 684 2006.12

Nucleotidase improves glomerular autoregulation in Thy-1 nephritic rats Reviewed

Takenaka Tsuneo, Okada Hirokazu, Kanno Yoshihiko, Inoue Tsutomu, Ryuzaki Munekazu, Nakamoto Hidetomo, Kawachi Hiroshi, Shimizu Fujio, Suzuki Hiromichi

JOURNAL OF HYPERTENSION 24 188 2006.12

Rat nephrin modulates cell morphology via the adaptor protein Nck Reviewed

Hongping Li, Jianxin Zhu, Lamine Aoudjit, Mathieu Latreille, Hiroshi Kawachi, Louise Larose, Tomoko Takano

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 349 ( 1 ) 310 - 316 2006.10

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

Nephrin is a transmembrane molecule essential for morphology and function of kidney podocytes. We and others reported previously that the cytoplasmic domain of human and mouse nephrin interacts with the adaptor protein, Nck, in a tyrosine phosphorylation-dependent manner. In the current study, we characterized the interaction of rat nephrin with Nck and further addressed its impact on cell morphology. Rat nephrin expressed in Cos-1 cells co-immunoprecipitated with Nck in a manner dependent on the phosphorylation of Y 1204 and Y 1228. Nephrin from normal rat glomeruli was also tyrosine phosphorylated and associated with Nck. Overexpression of rat nephrin in HEK293T cells induced morphological changes resembling process formation, which became more distinct when the extracellular domain of nephrin was cross-linked by antibodies. The morphological changes were attenuated by expression of dominant negative constructs of Nck. In the rat model of podocyte injury and proteinuria, nephrin tyrosine phosphorylation and nephrin-Nck interaction were both reduced significantly. Taken together, we propose that Nck couples nephrin to the actin cytoskeleton in glomerular podocytes and contributes to the maintenance of normal morphology and function of podocytes. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2006.08.053

Synaptic vesicle protein 2B is expressed in podocyte, and its expression is altered in proteinuric glomeruli Reviewed

Naoko Miyauchi, Akira Saito, Tamaki Karasawa, Yutaka Harita, Koichi Suzuki, Hiroko Koike, Gi Dong Han, Fujio Shimizu, Hiroshi Kawachi

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 17 ( 10 ) 2748 - 2759 2006.10

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

Synaptic vesicle protein 2B (SV2B) was identified by the subtraction hybridization technique as a molecule of which mRNA expression was decreased in puromycin aminonucleoside (PAN) nephropathy by glonterular cDNA subtraction assay. The expression of SV2B was detected in glomerular lysate with Western blot analysis. Dual-labeling immunofluorescence studies with glomerular cell markers demonstrated that SV2B is expressed in glomerular visceral epithelial cells (podocytes). The expression of SV2B is detected also in cultured podocyte and in human kidney section as podocytic pattern. The decrease of SV2B mRNA was already detected before the onset of proteinuria in PAN nephropathy. The mRNA expression of SV2B clearly is altered not only in PAN nephropathy but also in another proteinuric state that is caused by an antibody against nephrin, a functional molecule of the slit diaphragm. The decreased intensity in SV2B staining was already detected before the peak of proteinuria in both models with immunofluorescence study. A reduced amount of SV2B was detected in both models also with Western blot analysis. CD2AP, another functional molecule of the slit diaphragm, was observed in cytoplasm, including the processes area of the cultured podocyte, and when the podocyte was treated with small interfering RNA for SV2B, CD2AP staining at the process area was not detected. These results suggest that SV2B is a functional molecule of podocyte, and SV2B may play a role in the expression and proper localization of CD2AP.

DOI： 10.1681/ASN.2005121293

Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage Reviewed

Atsuhiro Ichihara, Yuki Kaneshiro, Tomoko Takemitsu, Mariyo Sakoda, Tsutomu Nakagawa, Akira Nishiyama, Hiroshi Kawachi, Fujio Shimizu, Tadashi Inagami

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 17 ( 9 ) 2495 - 2503 2006.9

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

Prorenin is activated without proteolysis by binding of prorenin receptor to the pentameric "handle region" (HR) of prorenin prosegment. It was hypothesized that such activation occurs in the kidneys of hypertensive rats and causes tissue renin-angiotensin system (RAS) activation and end-organ damage. Because the HR's binding to its binding protein made the adjacent tetrameric "gate region" (GR) accessible to its specific antibody, immunohistochemistry of the GR was performed to test the hypothesis. Methods also were devised specifically to inhibit the nonproteolytic activation by the decapeptide corresponding to the HR as a decoy. Immunohistochemistry of the GR demonstrated that the majority of nonproteolytically activated prorenin is present in podocytes of the kidneys from stroke-prone spontaneously hypertensive rats, in which activation of renal tissue RAS, proteinuria, and glomerulosclerosis occurred. Continuous subcutaneous administration of the HR decoy peptide completely inhibited both nonproteolytic activation of tissue prorenin and activation of tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of proteinuria and glomerulosclerosis. These studies clearly demonstrated that nonproteolytic activation of prorenin in glomeruli is critically involved in renal tissue RAS activation, leading to renal damage in hypertensive animals.

DOI： 10.1681/ASN.2005121278

Role of IP-10/CXCL10 in the progression of pancreatitis-like injury in mice after murine retroviral infection Reviewed

Yusuke Kawauchi, Kenji Suzuki, Shiro Watanabe, Satoshi Yamagiwa, Hiroyuki Yoneyama, Gi Dong Han, Suresh S. Palaniyandi, Punniyakoti T. Veeraveedu, Kenichi Watanabe, Hiroshi Kawachi, Yoshiaki Okada, Fujio Shimizu, Hitoshi Asakura, Yutaka Aoyagi, Shosaku Narumi

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 291 ( 2 ) G345 - G354 2006.8

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

Exocrinopathy and pancreatitis-like injury were developed in C57BL/6 (B6) mice infected with LP-BM5 murine leukemia virus, which is known to induce murine acquired immunodeficiency syndrome ( MAIDS). The role of chemokines, especially CXCL10/interferon (IFN)-gamma-inducible protein 10 (IP-10), a chemokine to attract CXCR3(+) T helper 1-type CD4(+) T cells, has not been investigated thoroughly in the pathogenesis of pancreatitis. B6 mice were inoculated intraperitoneally with LP-BM5 and then injected every week with either an antibody against IP-10 or a control antibody. Eight weeks after infection, we analyzed the effect of IP-10 neutralization. Anti-IP-10 antibody treatment did not change the generalized lymphadenopathy and hepatosplenomegaly of mice with MAIDS. The treatment significantly reduced the number of IP-10- and CXCR3-positive cells in the mesenteric lymph nodes (mLNs) but not the phenotypes and gross numbers of cells. In contrast, IP-10 neutralization reduced the number of mononuclear cells infiltrating into the pancreas. Anti-IP-10 antibody treatment did not change the numbers of IFN-gamma(+) and IL10(+) cells in the mLN but significantly reduced their numbers, especially IFN-gamma(+) and IL-10(+) CD4(+) T cells and IFN-gamma(+) Mac-1(+) cells, in the pancreas. IP-10 neutralization ameliorated the pancreatic lesions of mice with MAIDS probably by blocking the cellular infiltration of CD4(+) T cells and IFN-gamma(+) Mac-1(+) cells into the pancreas at least at 8 wk after infection, suggesting that IP-10 and these cells might play a key role in the development of chronic autoimmune pancreatitis.

DOI： 10.1152/ajpgi.00002.2006

Role of podocyte slit diaphragm as a filtration barrier Invited Reviewed

Hiroshi Kawachi, Naoko Miyauchi, Koichi Suzuki, Gi Dong Han, Michiaki Orikasa, Fujio Shimizu

NEPHROLOGY 11 ( 4 ) 274 - 281 2006.8

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

Although the role of glomerular basement membrane has been emphasised as the barrier for retaining plasma proteins in the past three decades, some recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Nephrin and podocin were identified as gene products mutated in Finnish-type congenital nephrotic syndrome and autosomal recessive steroid-resistant nephrotic syndrome, respectively. Nephrin s located at the outer leaflet of plasma membranes of the slit diaphragm. Podocin is reported to have an interaction with nephrin. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. The expression of nephrin and podocin was reduced in glomeruli of minimal change nephrotic syndrome, which suggested that the altered expression of these molecules contributes to the development of proteinuria also in acquired diseases. Some recent studies demonstrated that CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression is altered in membranous nephropathy. These observations suggested that alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases.

DOI： 10.1111/j.1440-1797.2006.00583.x

Transcription factor Ets-1 is essential for mesangial matrix remodeling Reviewed

M. Mizui, Y. Isaka, Y. Takabatake, Y. Sato, H. Kawachi, F. Shimizu, S. Takahara, T. Ito, E. Imai

KIDNEY INTERNATIONAL 70 ( 2 ) 298 - 305 2006.7

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

Most advanced glomerular diseases are characterized by abnormal extracellular matrix (ECM) accumulation in the glomeruli, and matrix metalloproteinases ( MMPs) play a pivotal role in ECM remodeling in various glomerular diseases. The proto-oncogene, ets-1, is a transcription factor regulating the expression of various matrix proteinases, including MMP-1, MMP-3, and MMP-9. The goal of the present study was to characterize the role of Ets-1 in the progression of glomerular diseases. Overexpression of Ets-1 in cultured mesangial cells prevented transforming growth factor (TGF)-beta-induced inhibition of DNA-binding activity and TGF-beta-induced type I collagen production. In addition, exogenous Ets-1 abolished TGF-beta-induced collagen gel contraction. The in vivo transfection of the ets-1 gene into nephritic kidney resulted in the increases in glomerular MMP-1, MMP-3, and MMP-9 mRNA, decreases in mesangial ECM deposition, and attenuation of fibronectin extradomain A (EDA) and type I collagen expression. In contrast, knockdown of Ets-1 in glomeruli resulted in severe ECM deposition in diseased glomeruli. In conclusion, Ets-1 promotes degradation of ECM proteins and is critical for integral glomerular reorganization.

DOI： 10.1038/sj.ki.5001541

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