Faculty Profiles - KAWACHI Hiroshi

Identification of hydroxyapatite deposits in the smooth muscle cells and ganglion cells of autopsied small intestines Reviewed

Hirotaka Tanabe, Takumi Akashi, Hiroshi Kawachi, Noboru Andou, Yoshinobu Eishi, Touichiro Takizawa, Morio Koike, Shizuko Ichinose

Journal of Medical and Dental Sciences 51 ( 2 ) 129 - 138 2004.6

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

We have studied the deposition of calcium salts in the autopsied intestines which have not been described previously as far as we were able to determine. In order to clarify the incidence, predisposing conditions, mineral compositions of the deposited materials and clinical significance of this phenomenon, we examined 76 cases of consecutive autopsied small intestines by von Kossa's staining. Deposited calcium salts were further examined by electron microscopically, energy-dispersive X-ray spectroscope and electron diffraction analysis. Deposition of calcium salts was observed in the small intestines of 13 cases. Among them, 10 cases were accompanied by hypercalcemia. Deposition of calcium salts was mainly observed in smooth muscle cells of the proper muscle layers and ganglion cells of the Auerbach's myenteric plexus. Intestinal calcinosis was frequently accompanied by deposition of calcium salts in the proper muscle layers of esophagus and large intestine, renal tubules and cardiac myocardial cells. Electron microscopically, the calcium salts were identified as needle-shaped crystals and located on the surface of the extracellular- collagen bundles, in the cytoplasm, mitochondria and nucleus of the smooth muscles cells. Energy-dispersive X-ray spectroscope and electron diffraction analysis suggested the deposited calcium salts as hydroxyapatite. Two patients among the six cases with moderate to severe calcium deposition showed clinical manifestation of paralytic ileus. In conclusion, intestinal calcinosis was frequently observed mostly associated with hypercalcemia. Calcium salts of hydroxyapatite were deposited to the smooth muscle cells and the Auerbach's myenteric plexus of the muscular layer. Deposition of calcium salts might occasionally causes the paralytic ileus but clinical significance of this lesion requires further examination.

Local Actions of Endogenous Angiotensin II in Injured Glomeruli Reviewed

Ji Ma, Taiji Matsusaka, Haichun Yang, Hiroshi Kawachi, Fujio Shimizu, Yoshitaka Isaka, Enyu Imai, Valentina Kon, Iekuni Ichikawa

Journal of the American Society of Nephrology 15 ( 5 ) 1268 - 1276 2004.5

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

A previous study showed that exogenous angiotensin II (AngII) induces proliferation of glomerular cells through systemic actions of AngII. In the present study, the authors examined the mode of actions of endogenous AngII in injured kidneys that were made deficient in AT1 by using in vivo transfection of antisense oligodeoxynucleotide (AS-ODN). Thy-1 nephritis was induced in rats by injection of mAb 1-22-3. Four days later, glomerular transfection was performed by unilateral whole-kidney electroporation after AT1 AS-ODN delivery through the left renal artery (n = 7). The expression of renal AT1 was assessed by autoradiography. The effect of the AS-ODN transfection was assessed 3 d later and compared with transfection with control ODN (n = 6), systemically administered pharmacologic AT1 antagonist losartan (n = 5) as well as untreated Thy-1 animals (n = 5). Fluorescence-labeled AS-ODN was found transfected in almost all glomeruli and localized primarily to the mesangium. Compared with the contralateral untransfected kidney in both normal and Thy-1 rats. AS-ODN suppressed cortical AT1 expression by some 70%. The AS-ODN transfected kidneys of Thy-1 rats had significantly lower glomerular mesangial cell proliferation (7.38 ± 0.68 cells/glomerulus) and extracellular matrix accumulation (0.262 ± 0.009) than kidneys transfected with control ODN (10.94 ± 0.51 cells/glomerulus and 0.342 ± 0.031), contralateral untransfected kidneys (9.56 ± 1.01 cells/glomerulus and 0.371 ± 0.011), or kidneys that were exposed to Thy-1 alone (10.45 ± 1.06 cells/glomerulus and 0.359 ± 0.013). There were no significant differences in systolic BP among groups. In glomeruli, immunohistochemistry detected no difference in AT2 receptor expression, number of ED1-positive macrophages or number of apoptotic cells among groups. Thus, in renal injury induced by Thy-1 nephritis, selective suppression of mesangial AT1 expression by ASODN significantly reduced mesangial cell proliferation and matrix. These data provide in vivo evidence that injured glomeruli are sensitive to local tissue actions of AngII, which promote proliferation and matrix accumulation within the glomerulus.

DOI： 10.1097/01.ASN.0000125675.70674.0F

Novel expression of sodium/myo-inositol co-transporter in podocytes in puromycin aminonucleoside nephrosis Reviewed

Y Watanabe, T Kobayashi, E Yaoita, H Kawachi, A Yamauchi, T Inoue, F Shimizu, Y Yoshida, AGA El-Shemi, H Okada, H Suzuki, T Yamamoto

NEPHROLOGY DIALYSIS TRANSPLANTATION 19 ( 4 ) 817 - 822 2004.4

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

Background. How podocytes respond to injury is poorly understood, although podocyte injury in the glomerulus has been proposed as the crucial mechanism in the pathogenesis of proteinuria and focal segmental glomerulosclerosis. An increase in sodium/myo-inositol co-transporter (SMIT) transcripts, an osmoprotective gene, has been demonstrated in a variety of brain injury models. In the present study, we investigated SMIT expression in podocytes in experimental nephrosis.
Methods. Two types of nephrosis were induced in rats: puromycin aminonucleoside (PAN) nephrosis and monoclonal antibody (mAb) 5-1-6 nephropathy. Podocyte injury was morphologically distinct in the former type of nephrosis and limited to a minimum in the latter. SMIT expression in isolated glomeruli was estimated by ribonuclease protection assay. Localization of SMIT-expressing cells in glomeruli was examined by in situ hybridization.
Results. WIT transcripts in glomeruli increased conspicuously in the nephrotic stage of PAN nephrosis, whereas the transcripts in cortices and medullae did not show significant changes. In situ hybridization revealed that podocytes were predominant cells expressing SMIT in the glomerulus. Significant increase of SMIT mRNA in the glomeruli was detected before the onset of massive proteinuria. In contrast, up-regulation of SMIT expression was not observed in mAb 5-1-6 nephropathy, whose urinary protein levels were comparable with those in the nephrotic stage of PAN nephrosis.
Conclusions. These findings suggest that SMIT expression in podocytes is not provoked by an effect of massive proteinuria but by extensive cellular injury.

DOI： 10.1093/ndt/gfh026

Decreased collagen-degrading activity could be a marker of prolonged mesangial matrix expansion Reviewed

Masayuki Tomita, Hiroko Koike, Gi Dong Han, Fujio Shimizu, Hiroshi Kawachi

Clinical and Experimental Nephrology 8 ( 1 ) 17 - 26 2004.3

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

Background. Mesangial matrix expansion is caused by the overproduction and/or the impaired proteolytic degradation of the extracellular matrix. However, the relative contribution of these changes to the development of prolonged mesangial matrix expansion is still poorly understood. We aimed to elucidate the relative role of the matrix metalloproteinase (MMP)/tissue inhibitors of metalloproteinases (TIMPs) system in the development of prolonged mesangial matrix expansion. Methods. We prepared two rat models, showing reversible or prolonged mesangial matrix expansion, induced by a single injection or two consecutive injections of anti-Thy-1.1 monoclonal antibody 1-22-3, respectively. We analyzed the glomerular expression of type I and type IV collagens
MMP-2, -9, and -13
membrane type 1-MMP (MT1-MMP)
TIMP-1
and urinary type I collagen-degrading activity in both models. Results. There were no differences in glomerular mRNA levels of type I and type IV collagens between the reversible and the prolonged models. MMP-9 mRNA expression and protein level was lower in the prolonged model than in the reversible one, whereas there were no differences in mMRNA levels of MMP-2, -13, MT1-MMP, or TIMP-1 between the two models. Urinary type I collagen-degrading activity in the prolonged model was lower than that in the reversible one. Furthermore, there was a significant correlation between the mesangial matrix expansion and urinary type I collagen-degrading activity. Conclusions. Impaired expression of MMP-9 may contribute to the development of prolonged mesangial matrix expansion. Analysis of urinary type I collagen-degrading activity may provide additional diagnostic information in mesangial proliferative glomerulonephritis.

DOI： 10.1007/s10157-003-0258-7

Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat Reviewed

M Schaier, S Liebler, K Schade, F Shimizu, H Kawachi, HJ Grone, R Chandraratna, E Ritz, J Wagner

JOURNAL OF MOLECULAR MEDICINE-JMM 82 ( 2 ) 116 - 125 2004.2

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

Retinoids, derivatives of vitamin A, inhibit mesangial cell proliferation, glomerular inflammation, and extracellular matrix deposition in acute anti-Thy1.1 glomerulonephritis (Thy-GN) of the rat. We examined a model, chronic mesangioproliferative Thy-GN (MoAb 1-22-3), which is more akin to human disease. Treatment started on day 23 when Thy-GN had already been established. Nonnephritic control and Thy-GN rats were treated orally for 67 days with vehicle or with two doses of either the retinoic acid receptor alpha-specific agonist AGN 195183 (RARalpha agonist) or the retinoid X receptor specific agonist AGN 194204 (RXR agonist). Doses of either the RARalpha or the RXR agonist significantly reduced albuminuria and normalized blood pressure during the course of treatment. The glomerulosclerosis index, glomerular cell and interstitial cell counts, and area of the interstitial space were significantly lower in nephritic rats treated with the RARalpha agonist or RXR agonist than with vehicle. The RARalpha and RXR agonist significantly reduced the infiltration of the glomerulus by macrophages. The increase in glomerular TGFbeta1 and prepro-ET1 gene expression in vehicle-treated nephritic rats was significantly attenuated by RARalpha or RXR agonists. Glomerular expression of RXRalpha and RARalpha receptor mRNA was significantly greater in vehicle-treated nephritic rats than in nonnephritic controls. Treatment with RARalpha or RXR agonists tended to normalize retinoid-receptor gene expression. Our data indicate that both RARalpha agonists and RXR agonists reduce renal damage in rats with established chronic glomerulonephritis. Receptor-specific retinoids may provide a novel therapeutic approach for the treatment of chronic glomerulonephritis.

DOI： 10.1007/s00109-003-0510-3

Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat Reviewed

BJ Davis, JM Forbes, MC Thomas, G Jerums, WC Burns, H Kawachi, TJ Allen, ME Cooper

DIABETOLOGIA 47 ( 1 ) 89 - 97 2004.1

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

Aims/hypothesis. Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension.
Method. Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks.
Results. Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFbeta1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine.
Conclusion/interpretation. These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury.

DOI： 10.1007/s00125-003-1256-8

The role of lymphocytes in the experimental progressive glomerulonephritis Reviewed

Yohei Ikezumi, Katsue Kanno, Tamaki Karasawa, G. I. Dong Han, Yumi Ito, Hiroko Koike, Shinichi Toyabe, Makoto Uchiyama, Fujio Shimizu, Hiroshi Kawachi

Kidney International 66 ( 3 ) 1036 - 1048 2004

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

Background. Glomerular accumulation of leukocytes, including lymphocytes, is a common feature in most types of glomerulonephritis. However, the role of lymphocytes in progressive glomerulonephritis has not been elucidated. We examined the role of lymphocytes in the development of progressive mesangial proliferative glomerulonephritis induced by two injections of monoclonal antibody 1-22-3 in rats. Methods. To elucidate the role of lymphocytes, circulating lymphocytes were depleted using specific monoclonal antibodies to rat lymphocytes prior to the induction of progressive glomerulonephritis. The effects of lymphocyte depletion on proteinuria and glomerular alterations were assessed 7 and 56 days after the induction of progressive glomerulonephritis. Results. Significant glomerular accumulation of CD4+ T cells, CD8+ T cells, and ED3+-activated macrophage were observed after the induction of glomerulonephritis. Depletion studies showed that continuous treatment with anti-CD5, anti-CD4, or anti-CD8 treatment reduced proteinuria and ameliorated the glomerular lesions on day 56. Depletion of CD4+ T cells also reduced glomerular accumulation of CD8+ T cells and ED3+-activated macrophages, and reduced glomerular expression of mRNA for interferon-gamma (INF-γ) (63.0% in anti-CD5 and 62.3% reduction in anti-CD4). Transit lymphocyte depletion limited in early stage of progressive glomerulonephritis demonstrated that CD4+ T-cell depletion, but not anti-CD8 treatment prevented glomerular injuries 56 days after the induction of progressive glomerulonephritis. Conclusion. CD4+ T cells played a central role in the development of progressive glomerulonephritis, controlling recruitment and activation of CD8+ cytotoxic cells and/or macrophages.

DOI： 10.1111/j.1523-1755.2004.00852.x

Moderate alcohol intake has no impact on acute and chronic progressive anti-Thy-1 glomerulonephritis Reviewed

Peters H, Martini S, Woydt R, Ruckert M, Shimizu F, Kawachi H, Liefeldt L, Kramer S, Neumayer HH

Am J Physio Renal Physiol 284 F1105 - F1114 2003.12

続々と登場する糸球体上皮細胞スリット膜関連分子-蛋白尿発現の分子機構解明に向けて Invited

河内裕

医学のあゆみ 206 287 - 288 2003.12

糸球体上皮細胞の機能因子最近明らかになった蛋白尿発症責任分子について Invited

河内裕

診断と治療 91 517 - 522 2003.12

IFN-inducible protein-10 has a differential role in podocyte during Thy 1.1 glomerulonephritis Reviewed

GD Han, H Koike, T Nakatsue, K Suzuki, H Yoneyama, S Narumi, N Kobayashi, P Mundel, F Shimizu, H Kawachi

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 ( 12 ) 3111 - 3126 2003.12

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

IFN-inducible protein-10 (IP-10/CXCL10) is a potent chemoattractant for activated T lymphocytes and was recently reported to have several additional biologic activities. In this study, the expression and the function in normal glomeruli and in Thy1.1 glomerulonephritis (GN) were investigated. The expression of IP-10 was detected in normal rat glomeruli mainly in the podocyte. The expression of IP-10 was also detected on the cultured podocyte. The IP-10 expression was elevated at the early phase of Thyl.1 GN. The double staining immunofluorescence study clearly demonstrated that the elevated expression of IP-10 was mostly detected in the podocyte and very partly in mesangial area. A receptor for IP-10, CXCR3, showed similar expression patterns to that of IP-10. Expressions of neither of IP-10 nor of CXCR3 were detected on the inflammatory cells. For elucidating the role of IP-10, the blocking study was carried out with monoclonal anti-IP-10 antibody. The monoclonal anti-IP-10 antibody treatment decreased the expression of IP-10 and podocyte associated proteins such as nephrin and podocin that are reported to be essential for maintaining the podocyte function (IP-10, 53.0% to control; nephrin, 43.5%; podocin, 60.4%). The findings indicated that the anti-IP-10 treatment disturbed the podocyte function. The anti-IP-10 treatment given to the rats with Thy1.1 nephritis exacerbated proteinuria, mesangiolysis, and matrix expansion. Collectively, the findings indicated that IP-10 plays a role in maintaining the podocyte function. Also, the findings suggested that anti-IP-10 treatment exacerbated the glomerular alterations in Thyl.1 GN by disturbing the podocyte function.

DOI： 10.1097/01.ASN.0000097371.64671.65

蛋白尿発現の分子機構：ネフリンのネフローゼ症候群における臨床的意義 Invited

スリット膜関連分子群の性状. Invited

河内裕

腎と透析 55 702 - 706 2003.12

蛋白尿発症の分子機構 Invited

河内裕

腎と透析 54 189 - 193 2003.12

蛋白尿の発症機序. Invited

河内裕

小児内科 35 815 - 819 2003.12

Urinary sediment podocalyxin in children with glomerular diseases Reviewed

Kanno K, Kawachi H, Uchida Y, Hara M, Shimizu F, Uchiyama M

Nephron Clin Pract 95 ( 3 ) c91 - c99 2003.12

清水不二雄, 河内裕

日本内科学会誌 92 ( 7 ) 159 - 165 2003.12

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

ラット腎糸球体上皮細胞(GEC)足突起間スリット膜に対する単クローン抗体投与によりラットに高度の蛋白尿が惹起されることやスリット膜構成分子ネフリンの遺伝子レベルにおける異常が重症の先天性ネフローゼ症候群をもたらすことなどから,スリット膜が,最終的に高分子透過阻止に関与することが明らかにされた.ネフリンが発端となり,ポドシン, CD2APなどGEC,とりわけスリット膜関達分子の遺伝子レベルにおける異常が蛋白尿ないし家族性の糸球体硬化症をもたらすことが相次いで報告されている.新しく登場する分子も含めたこれら諸分子の相互関係の解明をとうして, GECの構造・機能を制御する情報伝達系の詳細が明らかにされ,その結果,蛋白尿の合理的な抑制策の確立とそれによる慢性腎不全状態への進展阻止が可能となるものと期待され,その中心的な存在であるネフリンは新しい治療法開発への重要な鍵をにぎる対象として注目され続けていくと思われる.

DOI： 10.2169/naika.92.1337

CiNii Article

CiNii Books

Other Link： http://hdl.handle.net/10191/17972

Kinetic analysis of the development of pancreatic lesions in mice infected with a murine retrovirus Reviewed

S Watanabe, K Suzuki, Y Kawauchi, S Yamagiwa, H Yoneyama, H Kawachi, Y Okada, F Shimizu, H Asakura, Y Aoyagi

CLINICAL IMMUNOLOGY 109 ( 2 ) 212 - 223 2003.11

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

Sjogren's syndrome (SjS)-like sialoadenitis and exocrine pancreatitis were induced in mice infected with LP-BM5 murine leukemia virus, which induces a severe immunodeficiency termed murine AIDS (MAIDS). All mice with MAIDS showed advancing cellular infiltration around the pancreatic ducts as well as systemic exocrinopathy. The primary target tissue of the pancreas was acinar cells, and the pancreatic islets were well preserved until a late phase of the disease. Immunofluorescence and flow cytometry demonstrated that CD4(+) T cells, Mac-1(+) cells, and B220(+) cells were major inflammatory components, and IFN-gamma and IL-10 were mainly detected on CD4(+) T and Mac-1(+) cells in the pancreas. Both Th1 and Th2 cells were found. TUNEL+ apoptotic cells were mostly detected among pancreas-infiltrating cells. Fas ligand and TNF-alpha were also detected among pancreas-infiltrating cells, whereas Fas was rarely expressed in the pancreatic acinar cells. Thus, MAIDS mice could be valuable for analyzing the pathogenesis of autoimmume-related pancreatitis associated with SjS. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S1521-6616(03)00197-9

Monoclonal antibody against rat podocyte-derived macrophagic cells reacts with crescent-forming cells in an experimental model Reviewed

Michiaki Orikasa, Toshihiko Iwanaga, Hiroshi Kawachi, Akihisa Oyanagi, Ping Li, Qian Su, Hideo Kobayashi, Hitoshi Nakayama, Hiroshi Kikuchi, Fujio Shimizu

Nephrology 8 ( 5 ) 217 - 223 2003.10

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

The origin of crescent-forming cells in crescentic glomerulonephritis has not been clarified in spite of the application of monoclonal antibodies (mAbs) against glomerular epithelial cells or monocytes/macrophages. This study was undertaken to characterize the cellular composition of crescents using a new marker, mAb OS-3, produced against macrophagic cells derived from podocytes in normal rat glomerular culture. Monoclonal antibody OS-3 was confirmed to be reactive with some normal epithelial cells of Bowman's capsule. Female Wistar Kyoto rats were injected with rabbit anti-glomerular basement membrane (GBM) serum and killed at 2 h, 1, 3, 7, 14 days and 2 months, respectively. The mAb OS-3-positive cells were segmentally observed in glomeruli at 3 days, increased at 14 days, but decreased at 2 months. These cells lacked reactivity with antipodocalyxin in double immunofluorescence (IF) staining. In immunoelectron microscopy of a glomerulus on day 3 and 7, however, reaction products were observed within cells located on the outer surface of the GBM, which were considered to be podocyte in terms of its localization. In conclusion, we have shown a possibility that damaged podocytes partly constitute crescent-forming cells with phenotypic changes, visualized by positive staining with mAb OS-3. We propose a novel concept of crescent formation, suggesting that crescents may be partly composed of phenotypically changed cells, which could not be detected by typical markers for glomerular epithelial cells or monocytes/macrophages.

DOI： 10.1046/j.1440-1797.2003.00167.x

Genetic polymorphism of NPHS1 modifies the clinical manifestations of Ig a nephropathy Reviewed

Narita, I, S Goto, N Saito, J Song, D Kondo, K Omori, H Kawachi, F Shimizu, M Sakatsume, M Ueno, F Gejyo

LABORATORY INVESTIGATION 83 ( 8 ) 1193 - 1200 2003.8

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

Nephrin, the molecule responsible for congenital nephrotic syndrome of Finnish type, is crucial in maintaining the glomerular filtration barrier. Recently, its complete gene structure and common gene polymorphisms in its exons have been reported, although the functional and clinical significance of these polymorphisms has not yet been elucidated. We investigated a possible association of the NPHS1 polymorphisms with the development of Ig A nephropathy (IgAN), as well as the clinical and histologic manifestations in IgAN. A total of 464 Japanese subjects, including 267 patients with histologically proven IgAN and 197 healthy controls with normal urinalysis, were genotyped for the NPHS1 G349A, G2289A, and T3315C polymorphisms. The frequencies of the genotypes, alleles, and estimated haplotypes of NPHS1 polymorphisms were no different between patients with IgAN and the controls. Within the IgAN group, patients carrying at least one G allele of G349A tended to present with more proteinuria, lower renal function, and more severe histopathologic injury than those with the AA genotype, although the time from the first urinary abnormality to the renal biopsy was no different between both groups. The logistic regression analysis indicated that even after adjusting for the effect of proteinuria and hypertension the GG genotype of NPHS1 G349A was an independent risk factor for the deteriorated renal function at the time of diagnosis. This study suggests that the NPHS1 G349A polymorphism may be associated with heavy proteinuria and a decline in renal function in patients with IgAN.

DOI： 10.1097/01.LAB.0000080600.49276.31