Faculty Profiles - KAWACHI Hiroshi

Papers - KAWACHI Hiroshi

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Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium Reviewed

Kenji Suzuki, Xiaomei Sun, Masaki Nagata, Tomoyuki Kawase, Hana Yamaguchi, Vijayakumar Sukumaran, Yusuke Kawauchi, Hiroshi Kawachi, Takayoshi Nishino, Kenichi Watanabe, Hiroyuki Yoneyama, Hitoshi Asakura

Pathology International 61 ( 4 ) 228 - 238 2011.4

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

Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-β, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin +, α-smooth muscle actin (α-SMA) -) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin +, α-SMA +) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-β 1 substantially augmented the expressions of both vimentin and α-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model. © 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1827.2011.02647.x

A notable case report of May-Hegglin anomaly with immune complex-related nephropathy: a genetic and histological analysis

Y. Ohtsuka, T. Kanaji, M. Nish, N. Sakai, T. Sato, S. Aoki, K. Wakayama, S. Nakazato, S. Hisano, Y. Sado, H. Kawachi, K. Izuhara, Y. Hamasaki

CLINICAL NEPHROLOGY 75 ( 3 ) 255 - 262 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：DUSTRI-VERLAG DR KARL FEISTLE

May-Hegglin anomaly (MHA) is a rare autosomal dominant disease characterized by macrothrombocytopenia and leukocyte inclusions with microfilaments in the ribosomes. Mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA (NMMHC-IIA) have been identified in patients with MHA and other MYH9-related diseases. Two young males (an older and younger brother) presented with macrothrombocytopenia and leukocyte inclusion bodies. Electron microscopy (EM) revealed parallel filaments in leukocyte inclusion bodies characteristic of MHA. Immunofluorescence microscopy (IF) showed NMMHC-IIA antibodies in 1 - 2 leukocyte inclusion bodies. These findings were consistent with MHA and they were identified to express the MYH9 mutation, D1424H. The older brother underwent a renal biopsy because of persistent proteinuria. Histology revealed mesangial proliferative glomerulonephritis with granular deposits of IgG and CIq. EM showed that the dense deposits were located in subendothelial cells, mesangial cells and Bowman's capsule. Immunocytochemistry revealed that NMMHC-IIA antibodies were localized in podocyte and endothelial cells in the glomerulus. Moreover, the expression of nephrin and podocin, slit diagram protein, was normal. An inflammatory mechanism may occur separately from MYH9-related disease. This report presents a case of MHA with immune complex-related nephropathy.

DOI： 10.5414/CNP75255

CD28 superagonist-induced regulatory T cell expansion ameliorates mesangioproliferative glomerulonephritis in rats. Reviewed

Kenro Miyasato, Yoshitsugu Takabatake, Junya Kaimori, Tomonori Kimura, Harumi Kitamura, Hiroshi Kawachi, Xiao-Kang Li, Thomas Hünig, Shiro Takahara, Hiromi Rakugi, Yoshitaka Isaka

Clinical and experimental nephrology 15 ( 1 ) 50 - 7 2011.2

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

BACKGROUND: Naturally occurring regulatory T cells (Treg) are essential for the prevention of autoimmunity and overshooting immune responses to pathogens; however, the involvement of Treg in mesangioproliferative glomerulonephritis, a major cause of chronic kidney disease, remains unclear. Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of Treg in rats. METHOD: To confirm our hypothesis that CD28SA reduces the severity of experimental glomerulonephritis, anti-Thy1 nephritis model rats were treated with CD28SA or saline. RESULTS: CD28SA significantly suppressed the increase in proteinuria and serum creatinine levels. CD28SA-treated nephritic rats exhibited an increase in the infiltration of Treg in the glomeruli accompanied by infiltration of CD163-positive macrophages ("alternatively activated" macrophages). In addition, CD28SA significantly induced interleukin-10 mRNA expression in glomeruli, thereby ameliorating mesangial cell proliferation and extracellular matrix expansion. CONCLUSION: We established a new therapeutic approach to suppressing progressive glomerulonephritis. The therapeutic value of this approach warrants further attention and preclinical studies.

DOI： 10.1007/s10157-010-0370-4

Other Link： http://orcid.org/0000-0001-6508-4338

Neurexin-1, a presynaptic adhesion molecule, localizes at the slit diaphragm of the glomerular podocytes in kidneys Reviewed

Akira Saito, Naoko Miyauchi, Taeko Hashimoto, Tamaki Karasawa, Gi Dong Han, Mutsumi Kayaba, Tomoyuki Sumi, Masayuki Tomita, Yohei Ikezumi, Kenji Suzuki, Yasushi Koitabashi, Fujio Shimizu, Hiroshi Kawachi

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 300 ( 2 ) R340 - R348 2011.2

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

Saito A, Miyauchi N, Hashimoto T, Karasawa T, Han GD, Kayaba M, Sumi T, Tomita M, Ikezumi Y, Suzuki K, Koitabashi Y, Shimizu F, Kawachi H. Neurexin-1, a presynaptic adhesion molecule, localizes at the slit diaphragm of the glomerular podocytes in kidneys. Am J Physiol Regul Integr Comp Physiol 300: R340-R348, 2011. First published November 3, 2010; doi: 10.1152/ajpregu.00640.2009.-The slit diaphragm connecting the adjacent foot processes of glomerular epithelial cells (podocytes) is the final barrier of the glomerular capillary wall and serves to prevent proteinuria. Podocytes are understood to be terminally differentiated cells and share some common features with neurons. Neurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation. Although neurexin has been understood to be specifically expressed in neuronal tissues, we found that neurexin was expressed in several organs. Several forms of splice variants of neurexin-1 alpha were detected in the cerebrum, but only one form of neurexin-1 alpha was detected in glomeruli. Immunohistochemical study showed that neurexin restrictedly expressed in the podocytes in kidneys. Dual-labeling analyses showed that neurexin was colocalized with CD2AP, an intracellular component of the slit diaphragm. Immunoprecipitation assay using glomerular lysate showed that neurexin interacted with CD2AP and CASK. These observations indicated that neurexin localized at the slit diaphragm area. The staining intensity of neurexin in podocytes was clearly lowered, and their staining pattern shifted to a more discontinuous patchy pattern in the disease models showing severe proteinuria. The expression and localization of neurexin in these models altered more clearly and rapidly than that of other slit diaphragm components. We propose that neurexin is available as an early diagnostic marker to detect podocyte injury. Neurexin coincided with nephrin, a key molecule of the slit diaphragm detected in a presumptive podocyte of the developing glomeruli and in the glomeruli for which the slit diaphragm is repairing injury. These observations suggest that neurexin is involved in the formation of the slit diaphragm and the maintenance of its function.

DOI： 10.1152/ajpregu.00640.2009

Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion Reviewed

Yohei Ikezumi, Toshiaki Suzuki, Tamaki Karasawa, Hiroya Hasegawa, Takeshi Yamada, Naofumi Imai, Ichiei Narita, Hiroshi Kawachi, Kevan R. Polkinghorne, David J. Nikolic-Paterson, Makoto Uchiyama

HISTOPATHOLOGY 58 ( 2 ) 198 - 210 2011.1

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

Aims:
New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease.
Methods and results:
Biopsy specimens from paediatric (< 10 years, n = 14; > 12 years, n = 15) and adult (n = 27) IgAN showed a significant infiltrate of CD68+ macrophages. M2 macrophages, identified by CD163 or CD204 expression, were detected in glomeruli and the interstitium, being more prominent in adults versus young children. CD163+ and CD204+ macrophages were present in areas of fibrosis containing myofibroblasts, and double staining showed that CD163+ cells produced the profibrotic molecule, connective tissue growth factor. In young children, total CD68+ macrophages, but not M2 macrophages, correlated with glomerular hypercellularity. In contrast, in adults and older children, mesangial matrix expansion correlated with M2 macrophages but not with the total CD68+ macrophage infiltrate.
Conclusions:
Alternatively activated M2 macrophages are present in new-onset paediatric and adult IgAN, and this population may promote the development of fibrotic lesions.

DOI： 10.1111/j.1365-2559.2011.03742.x

Defective glycosylation of α-dystroglycan contributes to podocyte flattening Reviewed

Kenichiro Kojima, Hitonari Nosaka, Yuki Kishimoto, Yuri Nishiyama, Seiichi Fukuda, Masaru Shimada, Kenzo Kodaka, Fumiaki Saito, Kiichiro Matsumura, Teruo Shimizu, Tatsushi Toda, Satoshi Takeda, Hiroshi Kawachi, Shunya Uchida

Kidney International 79 ( 3 ) 311 - 316 2011

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

In addition to skeletal muscle and the nervous system, α-dystroglycan is found in the podocyte basal membrane, stabilizing these cells on the glomerular basement membrane. Fukutin, named after the gene responsible for Fukuyama-type congenital muscular dystrophy, is a putative glycosyltransferase required for the post-translational modification of α-dystroglycan. Chimeric mice targeted for both alleles of fukutin develop severe muscular dystrophy
however, these mice do not have proteinuria. Despite the lack of a functional renal defect, we evaluated glomerular structure and found minor abnormalities in the chimeric mice by light microscopy. Electron microscopy revealed flattening of podocyte foot processes, the number of which was significantly lower in the chimeric compared to wild-type mice. A monoclonal antibody against the laminin-binding carbohydrate residues of α-dystroglycan did not detect α-dystroglycan glycosylation in the glomeruli by immunoblotting or immunohistochemistry. In contrast, expression of the core α-dystroglycan protein was preserved. There was no statistical difference in dystroglycan mRNA expression or in the amount of nephrin and α3-integrin protein in the chimeric compared to the wild-type mice as judged by immunohistochemistry and real-time RT-PCR. Thus, our results indicate that appropriate glycosylation of α-dystroglycan has an important role in the maintenance of podocyte architecture. © 2011 International Society of Nephrology.

DOI： 10.1038/ki.2010.403

Ameliorating effects of L-carnitine on diabetic podocyte injury.

Fan Jiang Ping, Kim Dongyeop, Kawachi Hiroshi, Ha Tae-Sun, Han Gi Dong

J Med Food 13 ( 6 ) 1324 - 1330 2010.12

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

High glucose levels can change podocyte gene expression and subsequently induce podocyte damage through altered glucose metabolism. l-Carnitine is known to play a beneficial role in diabetes; however, there are no studies on the effects of l-carnitine on podocyte alteration under high glucose conditions. This study investigated whether l-carnitine can attenuate diabetic podocyte injury through the prevention of loss of slit diaphragm proteins. The l-carnitine treatment group showed increased glucose uptakes compared to the control group, suggesting that glucose utilization in the podocytes was increased by l-carnitine. l-Carnitine treatment also prevented decreased mRNA expressions of nephrin and podocin in the high glucose-stimulated podocytes. However, mRNA expressions of CD2AP and alpha-actinin-4 were not significantly changed by the high glucose conditions. When these data are taken together, l-carnitine can increase glucose uptake in podocytes under high glucose conditions, and its mechanism may be at least partly related to the up-regulation of nephrin and podocin. Our results help clarify the beneficial effects of l-carnitine in diabetic nephropathy.

DOI： 10.1089/jmf.2010.1079

Allogenic fetal membrane-derived mesenchymal stem cells contribute to renal repair in experimental glomerulonephritis. Reviewed

Tsuda H, Yamahara K, Ishikane S, Otani K, Nakamura A, Sawai K, Ichimaru N, Sada M, Taguchi A, Hosoda H, Tsuji M, Kawachi H, Horio M, Isaka Y, Kangawa K, Takahara S, Ikeda T

American journal of physiology. Renal physiology 299 ( 5 ) F1004 - 13 2010.11

p21-activated kinases regulate actin remodeling in glomerular podocytes

Jianxin Zhu, Ortal Attias, Lamine Aoudjit, Ruihua Jiang, Hiroshi Kawachi, Tomoko Takano

American Journal of Physiology - Renal Physiology 298 ( 4 ) F951 - F961 2010.4

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

The tyrosine phosphorylation of nephrin is reported to regulate podocyte morphology via the Nck adaptor proteins. The Pak family of kinases are regulators of the actin cytoskeleton and are recruited to the plasma membrane via Nck. Here, we investigated the role of Pak in podocyte morphology. Pak1/2 were expressed in cultured podocytes. In mouse podocytes, Pak2 was predominantly phosphorylated, concentrated at the tips of the cellular processes, and its expression and/or phosphorylation were further increased when differentiated. Overexpression of rat nephrin in podocytes increased Pak1/2 phosphorylation, which was abolished when the Nck binding sites were mutated. Furthermore, dominant-negative Nck constructs blocked the Pak1 phosphorylation induced by antibody-mediated cross linking of nephrin. Transient transfection of constitutively kinase-active Pak1 into differentiated mouse podocytes decreased stress fibers, increased cortical F-actin, and extended the cellular processes, whereas kinase-dead mutant, kinase inhibitory construct, and Pak2 knockdown by shRNA had the opposite effect. In a rat model of puromycin aminonucleoside nephrosis, Pak1/2 phosphorylation was decreased in glomeruli, concomitantly with a decrease of nephrin tyrosine phosphorylation. These results suggest that Pak contributes to remodeling of the actin cytoskeleton in podocytes. Disturbed nephrin-Nck-Pak interaction may contribute to abnormal morphology of podocytes and proteinuria. Copyrigh © 2010 the American Physiological Society.

DOI： 10.1152/ajprenal.00536.2009

Effects of mineralocorticoid and angiotensin II receptor blockers on proteinuria and glomerular podocyte protein expression in a model of minimal change nephrotic syndrome Reviewed

Akihiro Fukuda, Shouichi Fujimoto, Shuji Iwatsubo, Hiroshi Kawachi, Kazuo Kitamura

NEPHROLOGY 15 ( 3 ) 321 - 326 2010.4

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

Aim:
Several proteins constituting the slit diaphragm are considered important for maintaining capillary wall permselectivity. Early intervention with blockers of angiotensin II receptors (AR) and mineralocorticoid receptors (MR) is effective against proteinuria in models of chronic hypertensive and protein-induced renal damage. However, the effects of AR and/or MR blockers in a model of acute nephrotic syndrome remain unknown. The effects of AR and MR blockers were examined in puromycin aminonucleoside (PAN)-treated rats.
Methods:
Six week old male Sprague-Dawley (SD) rats were injected with PAN or vehicle and assigned to groups as follows: vehicle (group C); PAN (group P); PAN followed 3 days later by administration of the MR blocker, eplerenone (group MR), and by the AR blocker, losartan (group AR). Blood pressure and urinary protein excretion were measured and all rats were killed for immunohistochemical investigation on day 14 after PAN administration.
Results:
Blood pressure did not change throughout the study period. Proteinuria was decreased in groups MR and AR compared with group P (on day 14 after PAN administration, respectively; group P vs AR, P < 0.01; group P vs MR, P < 0.05). Nephrin, podocin and podocalyxin staining was preserved in the glomeruli of groups MR and AR compared with group P.
Conclusion:
The MR and AR blockers decreased proteinuria in the acute model of nephrotic syndrome with preserved expression of glomerular podocyte protein independently of blood pressure.

DOI： 10.1111/j.1440-1797.2009.01256.x

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. Reviewed International journal

Mari Tanaka, Misako Asada, Atsuko Y Higashi, Jin Nakamura, Akiko Oguchi, Mayumi Tomita, Sachiko Yamada, Nariaki Asada, Masayuki Takase, Tomohiko Okuda, Hiroshi Kawachi, Aris N Economides, Elizabeth Robertson, Satoru Takahashi, Takeshi Sakurai, Roel Goldschmeding, Eri Muso, Atsushi Fukatsu, Toru Kita, Motoko Yanagita

The Journal of clinical investigation 120 ( 3 ) 768 - 77 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.

DOI： 10.1172/JCI39569

Rectal administration of tranilast ameliorated acute colitis in mice through increased expression of heme oxygenase-1 Reviewed

Xiaomei Sun, Kenji Suzuki, Masaki Nagata, Yusuke Kawauchi, Masahiko Yano, Shogo Ohkoshi, Yasunobu Matsuda, Hiroshi Kawachi, Kenichi Watanabe, Hitoshi Asakura, Yutaka Aoyagi

PATHOLOGY INTERNATIONAL 60 ( 2 ) 93 - 101 2010.2

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

Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-a, interferon-g and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD.

DOI： 10.1111/j.1440-1827.2009.02490.x

ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive glomerulonephritis Reviewed

Maki Urushihara, Masanori Takamatsu, Maki Shimizu, Shuji Kondo, Yukiko Kinoshita, Kenichi Suga, Akiko Kitamura, Sato Matsuura, Masanori Yoshizumi, Toshiaki Tamaki, Hiroshi Kawachi, Shoji Kagami

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 298 ( 1 ) F167 - F176 2010.1

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

Urushihara M, Takamatsu M, Shimizu M, Kondo S, Kinoshita Y, Suga K, Kitamura A, Matsuura S, Yoshizumi M, Tamaki T, Kawachi H, Kagami S. ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive glomerulonephritis. Am J Physiol Renal Physiol 298: F167-F176, 2010. First published October 21, 2009; doi:10.1152/ajprenal.00124.2009.-The mitogen-activated protein kinase (MAPK) cascade plays an important role in the regulation of various cellular functions in glomerulonephritis (GN). Here, we investigated whether extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is involved in the pathogenesis of chronic mesangioproliferative GN, using a rat model induced by uninephrectomy and anti-Thy-1 antibody injection. Immunostaining of kidneys obtained at different time points revealed that phospho-ERK5 was weakly expressed in control glomeruli but dramatically increased in a typical mesangial pattern after 28 and 56 days of GN. A semiquantitative assessment indicated that glomerular phospho-ERK5 expression closely paralleled the accumulation of extracellular matrix (ECM), collagen type I, as well as glomerular expression of reactive oxygen species (ROS) and ANG II. On the other hand, phospho-ERK1/2 expression increased on day 7 during the phase of enhanced mesangial cell (MC) proliferation and decreased thereafter. H(2)O(2) and ANG II each induced ERK5 phosphorylation by cultured rat MCs. Costimulation with both H(2)O(2) and ANG II synergistically increased ERK5 phosphorylation in MCs. Cultured MCs transfected with ERK5-specific small interference RNA showed a significant decrease in H(2)O(2) or ANG II-induced cell viability and soluble collagen secretion compared with control cells. Treatment of GN rats with an ANG II type 1 receptor blocker resulted in significant decreases in phospho-ERK5 expression and collagen accumulation accompanied by remarkable histological improvement. Taken together, these results suggest that MC ERK5 phosphorylation by ANG II or H(2)O(2) enhances cell viability and ECM accumulation in an experimental model of chronic GN.

DOI： 10.1152/ajprenal.00124.2009

Rac1 Contributes to Actin Organization in Glomerular Podocytes

Ortal Attias, Ruihua Jiang, Lamine Aoudjit, Hiroshi Kawachi, Tomoko Takano

NEPHRON EXPERIMENTAL NEPHROLOGY 114 ( 3 ) E93 - E106 2010

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

Background/Aims: The function of glomerular podocytes is closely associated with the actin cytoskeleton. In this study, we studied the role of the small Rho-GTPase, Rac1, in actin organization in podocytes. Methods: Conditionally immortalized mouse podocytes (MP) stably expressing nephrin or control plasmid were used. Results: In MP, Rac1 activity increased significantly at 1 week of differentiation. MP stably expressing nephrin showed Rac1 activity significantly higher and more sustained than vector-expressing control cells. Antibody-mediated cross-linking of nephrin also activated Rac1. Differentiated MP showed more distinct lamellipodia/cellular processes, as compared with undifferentiated cells, which was further augmented by nephrin expression. Transient transfection of constitutively active Rac1 markedly increased the number of lamellipodia/cellular processes in undifferentiated MP, while the Rac1 inhibitor caused actin cytoskeleton derangement in differentiating MP. In the rat model of puromycin aminonucleoside nephrosis, RhoA activity was increased at Day 7 (at the peak of proteinuria), while Rac1 activity increased significantly only at Day 14, when the recovery process had started. Conclusion: Rac1 is activated in differentiating MP and nephrin potentiates Rac1 activation. Rac1 likely contributes to lamellipodia formation in differentiating MP and may contribute to process formation in podocytes recovering from injuries. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000262317

Peroxisome Proliferator-Activated Receptor-gamma Agonist Rosiglitazone Prevents Albuminuria but Not Glomerulosclerosis in Experimental Diabetes Reviewed

Giorgia Setti, Anthea Hayward, Cecile Dessapt, Francesca Barone, Robin Buckingham, Kathryn White, Rudolf Bilous, Kawachi Hiroshi, Gabriella Gruden, GianCarlo Viberti, Luigi Gnudi

AMERICAN JOURNAL OF NEPHROLOGY 32 ( 5 ) 393 - 402 2010

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

Backgrounds/Aims: Renal inflammation and nephrin downregulation contribute to albuminuria in diabetes. We studied, in streptozotocin-induced diabetic rats, the effect of rosiglitazone (RSG), a peroxisome proliferator-activated receptor-gamma agonist, on renal macrophage infiltration, MCP1, and nephrin expression in relation to albuminuria. Methods: We investigated control and diabetic rats treated or untreated with RSG. Animals were sacrificed at 1, 3, and 9 months. Renal MCP1 and nephrin expression were studied by immunoblotting, renal macrophage infiltration by immunohistochemistry, and albuminuria by ELISA. Electron microscopy was used to assess glomerular ultrastructural morphology. In vitro experiments were conducted in isolated cultured rat glomeruli. Results: Glycaemic control was similar in diabetic rats treated and untreated with RSG, and blood pressure was comparable in all groups. RSG prevented diabetes-induced albuminuria at 9 months, and renal macrophage infiltration and MCP1 upregulation at 3 and 9 months. Diabetes-mediated nephrin downregulation was abolished by RSG. Diabetes-induced glomerulosclerosis, glomerular basement membrane thickening, and foot process fusion were not affected by RSG. In isolated glomeruli, MCP1 directly induced nephrin downregulation and this was prevented by RSG. RSG had no effect on nephrin expression. Conclusion: RSG prevents albuminuria and nephrin downregulation in experimental diabetes independently of glycaemic and blood pressure control. This effect likely occurs via correction of diabetes-induced inflammatory processes. Copyright (C) 2010 S. Karger AG, Basel

DOI： 10.1159/000320129

Contrasting Effects of Steroids and Mizoribine on Macrophage Activation and Glomerular Lesions in Rat Thy-1 Mesangial Proliferative Glomerulonephritis Reviewed

Yohei Ikezumi, Toshiaki Suzuki, Tamaki Karasawa, Hiroya Hasegawa, Hiroshi Kawachi, David J. Nikolic-Paterson, Makoto Uchiyama

AMERICAN JOURNAL OF NEPHROLOGY 31 ( 3 ) 273 - 282 2010

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

Background: Macrophages with a pro-inflammatory (M1) phenotype mediate renal injury in proliferative forms of glomerulonephritis, while alternatively activated (M2) macrophages are thought to be anti-inflammatory and promote repair. Glucocorticoids, the mainstay therapy for proliferative glomerulonephritis, can induce alternative macrophage activation in vitro, but it is unknown whether this occurs in vivo and if this is required for glucocorticoid responsiveness. In addition, clinical studies have suggested that the ability of mizoribine (MZR) to suppress steroid-resistant proliferative glomerulonephritis may operate via inhibiting pro-inflammatory macrophage activation. Methods: This study examined prednisolone (PSL) and/or MZR treatment of rat Thy-1 disease - a model in which macrophages promote mesangial proliferative glomerulonephritis. Results: PSL treatment of Thy-1 nephritis induced an M2-like macrophage phenotype, but failed to modify mesangial hypercellularity and actually exacerbated global glomerulosclerosis. In contrast, MZR treatment reduced hypercellularity and glomerulosclerosis and suppressing both M1 and M2 markers of macrophage activation, with a selective reduction in CD169+ macrophages. Combined PSL/MZR treatment suppressed glomerular lesions and prevented steroid induction of an M2-like macrophage phenotype. In vitro, MZR prevented steroid induction of an M2 macrophage phenotype. Conclusions: Glucocorticoid induced alternative macrophage activation failed to ameliorate rat mesangial proliferative glomerulonephritis, whereas MZR suppression of this disease model was attributed, in part, to inhibition of M1-like proinflammatory macrophage activation. Copyright (C) 2010 S. Karger AG, Basel

DOI： 10.1159/000279163

Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats Reviewed

Tadashi Okada, Toshifumi Sakaguchi, Ikuji Hatamura, Fumie Saji, Shigeo Negi, Haruhisa Otani, Yasuteru Muragaki, Hiroshi Kawachi, Takashi Shigematsu

CLINICAL AND EXPERIMENTAL NEPHROLOGY 13 ( 5 ) 438 - 446 2009.10

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

Proteinuria caused by glomerular disease is characterized by podocyte injury. Vasopressin V2 receptor antagonists are effective in reducing albuminuria, although their actions on glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of tolvaptan, a selective oral V2 receptor antagonist, on podocytes in a puromycin aminonucleoside (PAN)-induced nephrosis rat model.
Rats were allocated to a control, PAN nephrosis, or tolvaptan-treated PAN nephrosis group (n = 9 per group). Urinary protein excretion and serum levels of total protein, albumin, creatinine, and total cholesterol were measured on day 10. The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy.
PAN induced massive proteinuria and serum creatinine elevation on day 10, both of which were significantly ameliorated by tolvaptan. Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats. In tolvaptan-treated rats, nephrin and podocin expressions retained their normal linear pattern. Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats.
Tolvaptan is protective against podocyte damage and proteinuria in PAN nephrosis. This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis. Tolvaptan is a promising pharmacological tool in the treatment of renal edema.

DOI： 10.1007/s10157-009-0196-0

Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats. International journal

Isao Matsui, Takayuki Hamano, Kodo Tomida, Kazunori Inoue, Yoshitsugu Takabatake, Yasuyuki Nagasawa, Noritaka Kawada, Takahito Ito, Hiroshi Kawachi, Hiromi Rakugi, Enyu Imai, Yoshitaka Isaka

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 24 ( 8 ) 2354 - 61 2009.8

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

BACKGROUND: Recent studies have demonstrated that podocyte injury, which results in proteinuria, leads to tubulointerstitial fibrosis. Although some studies have revealed that vitamin D administration protects renal structure and function in mesangial cell proliferative and/or excessive matrix productive models, the effects of vitamin D on podocyte injury have remained uncertain. METHODS: In this study, we examined whether administration of active vitamin D (calcitriol) or its analogue, 22-oxacalcitriol (maxacalcitol), is preventative in podocyte injury using the puromycin aminonucleoside nephrosis model with neither mesangial proliferation nor matrix accumulation. RESULTS: Before the onset of proteinuria, renal 1alpha-hydroxylase and 24-hydroxylase were markedly down-regulated and up-regulated, respectively, leading to impaired vitamin D activation. Thereafter, serum 25-hydroxyvitamin D decreased along with the increased excretion of vitamin D-binding protein in urine. After confirming that podocytes express vitamin D receptor and all retinoid X receptors (RXRs) except RXR-alpha, we found that daily administration of calcitriol or its analogue 22-oxacalcitriol ameliorated the nephrotic state by protecting podocytes, as shown by the reduced staining of desmin (podocyte injury marker) and the upregulation of nephrin and podocin. These data suggest that the impairment of the vitamin D system plays a role in increasing proteinuria in podocyte injury. CONCLUSIONS: We demonstrated the breakdown of the vitamin D activation system in podocyte injury, and established a preventative role for vitamin D in podocyte injury.

DOI： 10.1093/ndt/gfp117

Slit diaphragm dysfunction in proteinuric states: identification of novel therapeutic targets for nephrotic syndrome Reviewed

Hiroshi Kawachi, Koichi Suzuki, Naoko Miyauchi, Taeko Hashimoto, Yasuhiro Otaki, Fujio Shimizu

CLINICAL AND EXPERIMENTAL NEPHROLOGY 13 ( 4 ) 275 - 280 2009.8

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

Several recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the principal barrier in the glomerular capillary wall. Nephrin identified as a gene product mutated in congenital nephrotic syndrome located at the outer leaflet of plasma membranes of the slit diaphragm. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. Expression of nephrin was reduced in glomeruli of minimal change nephrotic syndrome. Some recent studies demonstrated that podocin, CD2-associated protein and NEPH1 are also functional molecules in the slit diaphragm, and their expressions are altered in membranous nephropathy and also in focal glomerulosclerosis. These observations suggested that the alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases. Recent studies of our group have demonstrated that type 1 receptor-mediated angiotensin II action reduced the expression of the slit diaphragm-associated molecules and that type 1 receptor blockade ameliorated proteinuria by preventing the function of angiotensin II on the slit diaphragm. By the subtraction hybridization techniques using glomerular cDNA of normal and proteinuric rats, we detected that synaptic vesicle protein 2B and ephrin B1 are involved in the maintenance of the barrier function of the slit diaphragm.

DOI： 10.1007/s10157-009-0162-x

Therapeutic targets in the podocyte: findings in anti-slit diaphragm antibody-induced nephropathy

Hiroshi Kawachi, Gi Dong Han, Naoko Miyauchi, Taeko Hashimoto, Koichi Suzuki, Fujio Shimizu

JOURNAL OF NEPHROLOGY 22 ( 4 ) 450 - 456 2009.7

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

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. Murine monoclonal antibody against nephrin, a molecule constituting the extracellular site of the slit diaphragm, caused severe proteinuria if injected into rats, in a complement- or inflammatory cell-independent manner. In this proteinuric state, not only nephrin but also other slit diaphragm-associated molecules are down-regulated. These observations suggest that the antibody alters the molecular composition of the slit diaphragm and, thereby, affects the glomerular permeability barrier. Recently, it was found that IP-10, SV2B, ephrin B1 and the receptors of angiotensin II were expressed in the podocyte, and that their expressions were clearly altered in anti-nephrin antibody-induced nephropathy. It is conceivable that these molecules are involved in the development of proteinuria in this model. IP-10 is assumed to play a role in maintaining the slit diaphragm function by regulating the cell cycle balance of the podocyte. SV2B and ephrin B1 play pivotal roles in the proper localization of the slit diaphragm component. In vivo and in vitro studies demonstrated that angiotensin II type 2 receptor-mediated action enhanced the expression of nephrin. We propose that these molecules could be novel therapeutic targets for proteinuria.

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