Papers - KAWACHI Hiroshi

Systematic implantation of dedifferentiated fat cells ameliorated monoclonal antibody 1-22-3-induced glomerulonephritis by immunosuppression with increases in TNF-stimulated gene 6

Takashi Maruyama, Noboru Fukuda, Taro Matsumoto, Koichiro Kano, Morito Endo, Minako Kazama, Tomohiko Kazama, Jin Ikeda, Hiroyuki Matsuda, Takahiro Ueno, Masanori Abe, Kazuyoshi Okada, Masayoshi Soma, Koichi Matsumoto, Hiroshi Kawachi

STEM CELL RESEARCH & THERAPY   6   2015.4

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Introduction: Implantation of mesenchymal stem cells (MSCs) has recently been reported to repair tissue injuries through anti-inflammatory and immunosuppressive effects. We established dedifferentiated fat (DFAT) cells that show identical characteristics to MSCs.
Methods: We examined the effects of 10(6) of DFAT cells infused through renal artery or tail vein on monoclonal antibody (mAb) 1-22-3-induced glomerulonephritis (as an immunological type of renal injury) and adriamycin-induced nephropathy (as a non-immunological type of renal injury) in rats. The mAb 1-22-3-injected rats were also implanted with 10(6) of DFAT cells transfected with TSG-6 siRNA through tail vein.
Results: Although DFAT cells transfused into blood circulation through the tail vein were trapped mainly in lungs without reaching the kidneys, implantation of DFAT cells reduced proteinuria and improved glomerulosclerosis and interstitial fibrosis. Implantation of DFAT cells through the tail vein significantly decreased expression of kidney injury molecule-1, collagen IV and fibronectin mRNAs, whereas nephrin mRNA expression was increased. Implantation of DFAT cells did not improve adriamycin-induced nephropathy, but significantly decreased the glomerular influx of macrophages, common leukocytes and pan T cells. However, the glomerular influx of helper T cells, was increased. Implantation of DFAT cells decreased expression of interleukin (IL)-6 and IL-12 beta mRNAs and increased expression of TNF-stimulated gene (TSG)-6 mRNA in renal cortex from mAb 1-22-3-injected rats. The basal level of TSG-6 protein was significantly higher in DFAT cells than in fibroblasts. Expression of TSG-6 mRNA in MCs cocultured with DFAT cells was significantly higher than in mesangial cells or DFAT cells alone. Systematic implantation of DFAT cells with TSG-6 siRNA through tail vein did not improve proteinuria, renal dysfunction and renal degeneration in the mAb 1-22-3-injected rats.
Conclusion: Systematic implantation of DFAT cells effectively ameliorated mAb 1-22-3-induced glomerulonephritis through immunosuppressive effects accompanied by the suppression of macrophage infiltration and expression of IL-6, IL-10 and IL-12 beta, and increased production of serum and renal TSG-6 that improved the mAb 1-22-3-induced renal degeneration by the immunosuppressive effects of TSG-6. Thus DFAT cells will be suitable cell source for the treatment of immunological progressive renal diseases.

DOI： 10.1186/s13287-015-0069-2

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ループス腎炎におけるポドサイト関連分子とカルシニューリンの変化

若松 彩子, 和田 庸子, 野澤 由貴子, 佐藤 弘恵, 中枝 武司, 今井 直史, 中野 正明, 河内 裕, 成田 一衛

日本腎臓学会誌   57 ( 3 )   484 - 484   2015.4

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin Reviewed

Aya Takahashi, Yoshiyasu Fukusumi, Mihoko Yamazaki, Mutsumi Kayaba, Yukina Kitazawa, Masayuki Tomita, Hiroshi Kawachi

JOURNAL OF NEPHROLOGY   27 ( 6 )   627 - 634   2014.12

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

The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain.
The glomerular expressions of the slit diaphragm (SD) molecules nephrin, podocin and NEPH1 in rat puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, were analyzed. The effects of Ang II receptor blockade (ARB) (irbesartan 15 mg/kg body weight/day) on proteinuria and on the expression of the SD molecules were analyzed.
mRNA expressions of nephrin, podocin and NEPH1 were decreased to an undetectable level at 1 h. The staining of these SD molecules shifted to a discontinuous pattern, and their intensity was reduced. NEPH1 staining was reduced to an undetectable level on day 10. ARB treatment ameliorated the peak value of proteinuria (237.6 +/- A 97.0 vs. 359.0 +/- A 63.3 mg/day, p < 0.05), and prevented the decrease in the mRNA expression of the SD molecules (nephrin 66.96 %, podocin 60.40 %, NEPH1 77.87 % of normal level). The immunofluorescence staining of NEPH1 was restored by ARB. ARB treatment enhanced the expression of NEPH1 of normal rats.
Dysfunction of the SD molecules including NEPH1 is a crucial initiation event of PAN nephropathy. ARB treatment ameliorates proteinuria in PAN nephropathy by inhibiting the reduction of NEPH1 and nephrin. Ang II action regulates the expression of NEPH1 and nephrin in not only the pathological but also physiological state.

DOI： 10.1007/s40620-014-0147-z

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Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules. International journal

Fukusumi Yoshiyasu, Miyauchi Naoko, Hashimoto Taeko, Saito Akira, Kawachi Hiroshi

World J Nephrol   3 ( 3 )   77 - 84   2014.8

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The slit diaphragm bridging the neighboring foot processes functions as a final barrier of glomerular capillary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Nephrin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an extracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2, a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient receptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of proteinuria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside nephropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier function. These molecules could be targets to establish a novel therapy for nephrotic syndrome.

DOI： 10.5527/wjn.v3.i3.77

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Therapeutic effect of anti-C-X-C motif chemokine 10 (CXCL10) antibody on C protein-induced myositis mouse Reviewed

Jinhyun Kim, Ji Y. Choi, Sung-Hye Park, Seung H. Yang, Ji A. Park, Kichul Shin, Eun Y. Lee, Hiroshi Kawachi, Hitoshi Kohsaka, Yeong W. Song

Arthritis Research and Therapy   16 ( 3 )   2014.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Introduction: C-X-C motif chemokine 10 (CXCL10) is a chemokine that plays a critical role in the infiltration of T cells in autoimmune diseases and is reported to be expressed in muscle tissue of polymyositis. To determine the therapeutic efficacy of CXCL10 blockade, we investigated the role of CXCL10 and the effect of anti-CXCL10 antibody treatment in C protein-induced myositis (CIM), an animal model of polymyositis.Methods: CIM was induced with human skeletal muscle C protein fragment in female C57BL/6 mice. Immunohistochemistry of CXCL10 and C-X-C motif chemokine receptor 3 (CXCR3) and measurement of serum CXCL10 were performed. Cell surface markers and interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in CIM lymph node cells was investigated by flow cytometry. Mice with CIM were treated with anti-CXCL10 antibody or control antibody (anti-RVG1) and the inflammation in muscle tissue was assessed.Results: Immunohistochemistry showed increased expression of CXCL10 and CXCR3 in the inflammatory lesions of muscle in CIM. Especially, CD8+ T cells invading myofiber expressed CXCR3. Serum level of CXCL10 was increased in CIM compared to the level in normal mice (normal mouse, 14.3 ± 5.3 pg/ml vs. CIM, 368.5 ± 135.6 pg/ml, P &lt
0.001). CXCR3 positivity in CD8+ T cells was increased compared to that of CD4+ T cells in the lymph node cells of CIM (CXCR3+ among CD8+ T cell, 65.9 ± 2.1% vs. CXCR3+ among CD4+ T cell, 23.5 ± 4.7%, P &lt
0.001). Moreover, IFN-γ+ cells were increased among CXCR3+CD8+ T cells compared to CXCR3-CD8+ T cells (CXCR3+CD8+ T cell, 28.0 ± 4.2% vs. CXCR3-CD8+ T cell, 9.5 ± 1.5%, P = 0.016). Migration of lymph node cells was increased in response to CXCL10 (chemotactic index was 1.91 ± 0.45). CIM mice treated with anti-CXCL10 antibody showed a lower inflammation score in muscles than those with anti-RVG1 (median, anti-CXCL10 treatment group, 0.625 vs. anti-RVG1 treatment group, 1.25, P = 0.007).Conclusions: CXCL10/CXCR3 expression was increased in the inflammation of CIM model and its blockade suppressed inflammation in muscle. © 2014 Kim et al.
licensee BioMed Central Ltd.

DOI： 10.1186/ar4583

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Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury

Sachiko Yamada, Jin Nakamura, Misako Asada, Masayuki Takase, Taiji Matsusaka, Taku Iguchi, Ryo Yamada, Mari Tanaka, Atsuko Y. Higashi, Tomohiko Okuda, Nariaki Asada, Atsushi Fukatsu, Hiroshi Kawachi, Daniel Graf, Eri Muso, Toru Kita, Takeshi Kimura, Ira Pastan, Aris N. Economides, Motoko Yanagita

PLOS ONE   9 ( 2 )   e89135 - e89135   2014.2

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Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

DOI： 10.1371/journal.pone.0089135

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Tyrosine kinases inhibition by Imatinib slows progression in chronic anti-thy1 glomerulosclerosis of the rat Reviewed

Yingrui Wang-Rosenke, Dymtro Khadzhynov, Tanja Loof, Alice Mika, Hiroshi Kawachi, Hans-H Neumayer, Harm Peters

BMC NEPHROLOGY   14   2013.10

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Background: Chronic progressive mesangioproliferative nephropathy represents a major cause of end-stage renal disease worldwide. Until now, effective approaches to stop or even slow its progression are limited. We tested the effects of an inhibitor of PDGF receptor, abl and c-kit tyrosine kinases, Imatinib, in a chronic progressive model of mesangioproliferative glomerulosclerosis.
Methods: Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, according to the degree of proteinuria, animals were stratified and assigned to chronic glomerulosclerosis (cGS) and cGS plus Imatinib (10 mg/kg body weight/day). In week 20, renoprotective actions of Imatinib were analyzed by a set of functional, histological and molecular biological parameters.
Results: Untreated cGS rats showed elevation of systolic blood pressure and marked progression in proteinuria, renal fibrosis, cell infiltration, cell proliferation and function lost. Administration of Imatinib went along significantly with lower systolic blood pressure (-10 mmHg) and proteinuria (-33%). Imatinib administration was paralled by significant reductions in tubulointerstitial accumulation of matrix proteins (-44%), collagen I deposition (-86%), expression of TGF-beta1 (-30%), production of fibronectin (-23%), myofibroblast differentiation (-87%), macrophage infiltration (-36%) and cell proliferation (-45%), respectively. In comparison with untreated cGS animals, Imatinib therapy lowered also blood creatinine (-41%) and blood urea concentrations (-36%) and improved creatinine clearance (+25%). Glomerular fibrotic changes were lowered moderately by Imatinib.
Conclusions: Therapy with Imatinib limits the progressive course of chronic anti-thy1 glomerulosclerosis towards tubulointerstitial fibrosis and renal insufficiency. This was paralleled by direct and indirect sign of TGF-beta 1 and PDGF inhibition. The findings suggest that the pharmacological principal of inhibition of tyrosine kinases with drugs such as Imatinib might serve as approach for limiting progression of human mesangioproliferative glomerulosclerosis.

DOI： 10.1186/1471-2369-14-223

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Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway Reviewed

Vivian Soetikno, Flori R. Sari, Arun P. Lakshmanan, Somasundaram Arumugam, Meilei Harima, Kenji Suzuki, Hiroshi Kawachi, Kenichi Watanabe

MOLECULAR NUTRITION & FOOD RESEARCH   57 ( 9 )   1649 - 1659   2013.9

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

Scope: We hypothesized that curcumin, by increasing the expression of nuclear factor-erythroid-2-related factor 2 (Nrf2), could reduce oxidative stress, inflammation, and renal fibrosis in remnant kidney.
Methods and resultsSprague-Dawley rats were subjected to 5/6 nephrectomy and randomly assigned to untreated (Nx), curcumin-treated (75 mg/kg/day, orally), and telmisartan-treated groups (10 mg/kg/day, orally; as positive control). Sham-operated rats also served as controls. Five/sixth nephrectomy caused renal dysfunction, as evidenced by elevated proteinuria, blood urea nitrogen, and plasma creatinine, and decreased creatinine clearance that were ameliorated by curcumin or telmisartan treatment. The Nx rats demonstrated reduced Nrf2 protein expression, whereas the Kelch-like ECH-associated protein 1 was upregulated and heme oxygenase-1 level was significantly diminished. Consequently, Nx animals had significantly higher kidney malondialdehyde concentration and lower glutathione peroxidase activity, which was associated with the upregulation of nicotinamide adenine dinucleotide phosphatase oxidase subunit (p67(phox) and p22(phox)), NF-kappaB p65, TNF-, TGF-1, cyclooxygenase-2, and fibronectin accumulation in remnant kidney. Interestingly, all of these changes were ameliorated by curcumin or telmisartan.
ConclusionThese findings demonstrate that, by modulating Nrf2-Keap1 pathway, the curcumin effectively attenuates oxidative stress, inflammation, and renal fibrosis, which suggest that curcumin hold promising potential for safe treatment of chronic kidney disease.

DOI： 10.1002/mnfr.201200540

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Planar cell polarity pathway regulates nephrin endocytosis in developing podocytes Reviewed

Sima Babayeva, Brittany Rocque, Lamine Aoudjit, Yulia Zilber, Jane Li, Cindy Baldwin, Hiroshi Kawachi, Tomoko Takano, Elena Torban

Journal of Biological Chemistry   288 ( 33 )   24035 - 24048   2013.8

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Background: The PCP pathway controls many cell processes during development. Results: The PCP pathway induces nephrin endocytosis when cultured podocytes are treated with Wnt5a. Loss of PCP protein Vangl2 decreases nephrin endocytosis. Conclusion: During glomerular development, endocytosis of nephrin is regulated by the PCP pathway. Significance: Implicating the PCP pathway in nephrin endocytosis is important for understanding the complexity of PCP signaling during mammalian development. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M113.452904

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Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats

Vivian Soetikno, Flori R. Sari, Vijayakumar Sukumaran, Arun Prasath Lakshmanan, Meilei Harima, Kenji Suzuki, Hiroshi Kawachi, Kenichi Watanabe

Journal of Nutritional Biochemistry   24 ( 5 )   796 - 802   2013.5

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Diabetic kidney disease has been associated with the presence of lipid deposits. We assumed that curcumin, a polyphenol, would attenuate the tissue dyslipidemic condition through activation of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and suppression of sterol regulatory element-binding protein (SREBP)-1c in the kidney and would prevent renal progression in experimental type 1 diabetic rats. Diabetes was induced with streptozotocin (STZ) (55 mg/kg) by intraperitoneal injection in male Sprague-Dawley rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic and diabetic treated with curcumin (100 mg/kg/day) by gavage for 8 weeks. We found that curcumin decreased plasma triglyceride and the amount of renal triglyceride significantly. Furthermore, treatment of diabetic rats with curcumin increased the phosphorylation of AMPK and prevented the increased renal expression of SREBP-1c and, as a result, decreased the expression of acetyl CoA carboxylase and fatty acid synthase as well as adipose differentiation-related protein, a marker of cytoplasmic droplets. We also demonstrate that curcumin significantly suppressed the increased expression of transforming growth factor β, vascular endothelial growth factor and extracellular matrix proteins such as type IV collagen and fibronectin. In addition, curcumin treatment increased nephrin expression to near-normal levels in diabetic rats. These results demonstrated that curcumin protects against the development of diabetic nephropathy through the AMPK-SREBP pathway and the reduction of renal triglyceride accumulation which could be a possible mechanism by which curcumin preserves renal function in diabetes. © 2013 Elsevier Inc.

DOI： 10.1016/j.jnutbio.2012.04.013

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The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic-non-obese type 2 diabetic rats: A differential role of unfolded protein response (UPR) signaling proteins Reviewed

Arun Prasath Lakshmanan, Meilei Harima, Kenji Suzuki, Vivian Soetikno, Masaki Nagata, Takashi Nakamura, Toshihiro Takahashi, Hirohito Sone, Hiroshi Kawachi, Kenichi Watanabe

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY   45 ( 2 )   438 - 447   2013.2

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

It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Toni (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm-of UPR signaling proteins, such as p-PERK, p-eIF2 alpha, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1 alpha, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPAR alpha, PPAR gamma, CPT1, PGC-1 alpha except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1 alpha-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM. (c) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.biocel.2012.09.017

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Development of lymphatic vasculature and morphological characterization in rat kidney Reviewed

Maki Tanabe, Akira Shimizu, Yukinari Masuda, Mitue Kataoka, Arimi Ishikawa, Kyoko Wakamatsu, Akiko Mii, Emiko Fujita, Seiichiro Higo, Tomohiro Kaneko, Hiroshi Kawachi, Yuh Fukuda

Clinical and Experimental Nephrology   16 ( 6 )   833 - 842   2012.12

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Background: The mechanisms and morphological characteristics of lymphatic vascular development in embryonic kidneys remain uncertain. Methods: We examined the distribution and characteristics of lymphatic vessels in developing rat kidneys using immunostaining for podoplanin, prox-1, Ki-67, type IV collagen (basement membrane: BM), and α-smooth muscle actin (αSMA: pericytes or mural cells). We also examined the expression of VEGF-C. Results: At embryonic day 17 (E17), podoplanin-positive lymphatic vessels were observed mainly in the kidney hilus. At E20, lymphatic vessels extended further into the developing kidneys along the interlobar vasculature. In 1-day-old pups (P1) to P20, lymphatic vessels appeared around the arcuate arteries and veins of the kidneys, with some reaching the developing cortex via interlobular vessels. In 8-week-old adult rats, lymphatic vessels were extensively distributed around the blood vasculature from the renal hilus to cortex. Only lymphatic capillaries lacking continuous BM and αSMA-positive cells were present within adult kidneys, with none observed in renal medulla. VEGF-C was upregulated in the developing kidneys and expressed mainly in tubules. Importantly, the developing lymphatic vessels were characterized by endothelial cells immunopositive for podoplanin, prox-1, and Ki-67, with no surrounding BM or αSMA-positive cells. Conclusion: During nephrogenesis, lymphatic vessels extend from the renal hilus into the renal cortex along the renal blood vasculature. Podoplanin, prox-1, Ki-67, type IV collagen, and αSMA immunostaining can detect lymphatic vessels during lymphangiogenesis. © 2012 Japanese Society of Nephrology.

DOI： 10.1007/s10157-012-0637-z

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Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis

Ayako Sato, Hoglan Piao, Yukiko Nozawa, Tetsuo Morioka, Hiroshi Kawachi, Takashi Oite

Clinical and Experimental Nephrology   16 ( 4 )   539 - 548   2012.8

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Background: Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN. Methods: Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system. Results: Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS + aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels. Conclusion: This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis. © 2012 Japanese Society of Nephrology.

DOI： 10.1007/s10157-012-0601-y

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Irsogladine maleate ameliorates infl ammation and fi brosis in mice with chronic colitis induced by dextran sulfate sodium

Hana Yamaguchi, Kenji Suzuki, Masaki Nagata, Tomoyuki Kawase, Vijayakumar Sukumaran, Rajarajan A. Thandavarayan, Yusuke Kawauchi, Junji Yokoyama, Masayuki Tomita, Hiroshi Kawachi, Kenichi Watanabe, Hiroyuki Yoneyama, Hitoshi Asakura, Ritsuo Takagi

Medical Molecular Morphology   45 ( 3 )   140 - 151   2012.6

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Intestinal fi brosis is a common and severe complication of infl ammatory bowel disease (IBD), especially Crohn's disease (CD). To investigate the therapeutic approach to intestinal fi brosis, we have developed a mouse model of intestinal fi brosis by administering dextran sulfate sodium (DSS) and examining the effects of irsogladine maleate (IM) [2,4-diamino-6-(2,5- dichlorophenyl)-s-triazine maleate], which has been widely used as an antiulcer drug for gastric mucosa in Japan, on DDS-induced chronic colitis. In this experimental colitis lesion, several pathognomonic changes were found: increased deposition of collagen, increased number of profi brogenic mesenchymal cells such as fi broblasts (vimentin+, 〈-SMA) and myofi broblasts (vimentin+, 〈-SMA+) in both mucosa and submucosa of the colon with infi ltrating infl ammatory cells, and increased mRNA expressions of collagen type I, transforming growth factor (TGF)-®, matrix metalloproteinase (MMP)-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1. When IM was administered intrarectally to this colitis, all these pathological changes were signifi cantly decreased or suppressed, suggesting a potential adjunctive therapy for intestinal fi brosis. IM could consequently reduce fi brosis in DSS colitis by direct or indirect effect on profi brogenic factors or fi broblasts. Therefore, the precise effect of IM on intestinal fi brosis should be investigated further. © 2012 The Japanese Society for Clinical Molecular Morphology.

DOI： 10.1007/s00795-011-0550-7

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Early treatment with everolimus exerts nephroprotective effect in rats with adriamycin-induced nephrotic syndrome Reviewed

Rawi Ramadan, Diana Faour, Hoda Awad, Eleanor Khateeb, Ravit Cohen, Ali Yahia, Rafael Torgovicky, Raanan Cohen, David Lazari, Hiroshi Kawachi, Zaid Abassi

Nephrology Dialysis Transplantation   27 ( 6 )   2231 - 2241   2012.6

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Background. Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria and excessive fluid retention. The effects of early versus late treatment with low or high doses of oral everolimus, a mammalian target of rapamycin inhibitor, on proteinuria in NS have not been previously described.Methods.The effects of early treatment (2 days prior to NS induction) versus late treatment (beginning 2 weeks following the establishment of NS) with a low (20 mg/L) or high (100 mg/L) dose of everolimus for 5-7 weeks on proteinuria and nephrin/podocin abundance were assessed in male adult SD rats with adriamycin-induced NS.Results.Adriamycin caused a significant increase in daily and cumulative proteinuria throughout the experimental period. Early, and to a lesser extent late treatment, with a low dose of everolimus, significantly decreased both daily and cumulative proteinuria and improved renal function. The anti-proteinuric effects of low-dose everolimus were associated with restoration of the disruptive glomerular nephrin/podocin abundance. In contrast, administration of a high dose of everolimus resulted in a decrease in proteinuria in NS rats, subsequently to deterioration of renal function.Conclusions.Early, and to a lesser extent late treatment, with a low but not a high dose of everolimus is effective in reducing proteinuria in nephrotic rats. The mechanism may be via nephrin/podocin protection. © 2012 The Author.

DOI： 10.1093/ndt/gfr581

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Early treatment with olmesartan prevents juxtamedullary glomerular podocyte injury and the onset of microalbuminuria in type 2 diabetic rats. International journal

Tadashi Sofue, Hideyasu Kiyomoto, Hiroyuki Kobori, Maki Urushihara, Yoko Nishijima, Kumiko Kaifu, Taiga Hara, Sachiko Matsumoto, Atsuhiko Ichimura, Hiroyuki Ohsaki, Hirofumi Hitomi, Hiroshi Kawachi, Melvin R Hayden, Adam Whaley-Connell, James R Sowers, Sadayoshi Ito, Masakazu Kohno, Akira Nishiyama

American journal of hypertension   25 ( 5 )   604 - 11   2012.5

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BACKGROUND: Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus. METHODS: OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7-25 weeks. RESULTS: OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters. CONCLUSIONS: This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.

DOI： 10.1038/ajh.2012.1

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Successful treatment of icodextrin-single peritoneal dialysis for refractory nephrotic syndrome induced by idiopathic membranous nephropathy. Reviewed

Takada D, Mii A, Higo S, Obara Y, Kurabayashi Y, Kurosawa N, Miura S, Kawachi H, Shimizu A

CEN case reports   1 ( 1 )   16 - 23   2012.5

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DOI： 10.1007/s13730-012-0006-5

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Proteinuria in AMPD2-deficient mice Reviewed

Toyama Keiko, Morisaki Hiroko, Cheng Jidong, Kawachi Hiroshi, Shimizu Fujio, Ikawa Masahito, Okabe Masaru, Morisaki Takayuk

Genes To Cells   17 ( 1 )   28 - 38   2012

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The AMPD2 gene, a member of the AMPD gene family encoding AMP deaminase, is widely expressed in nonmuscle tissues including kidney, although its functions have not been fully elucidated. In this study, we studied the function of the AMPD2 gene by establishing AMPD2-deficient model animal. We established AMPD2 knockout mice by using gene transfer and homologous recombination in murine ES cells and studied phenotypes and functions in the kidneys of these animals. AMPD activity was decreased from 22.9mIU/mg protein to 2.5mIU/mg protein in the kidneys of AMPD knockout mice. In addition to changes in nucleotide metabolism in the kidneys, proteinuria was found in 3-week-old AMPD2 knockout mice, followed by a further increment up to a peak level at 6weeks old (up to 0.6g/dL). The major protein component in the urine of AMPD2 knockout mice was found to be albumin, indicating that AMPD2 may have a key role in glomerular filtration. Indeed, an ultrastructure study of glomerulus specimens from these mice showed effacement of the podocyte foot processes, resembling minimal-change nephropathy in humans. Based on our results, we concluded that AMPD2 deficiency induces imbalanced nucleotide metabolism and proteinuria, probably due to podocyte dysfunction. © 2012 The Authors. Journal compilation © 2012 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2443.2011.01568.x

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Angiotensin II type I receptor blockade suppresses glomerular renin-angiotensin system activation, oxidative stress, and progressive glomerular injury in rat anti-glomerular basement membrane glomerulonephritis Reviewed

Yukiko Kinoshita, Shuji Kondo, Maki Urushihara, Kenichi Suga, Sato Matsuura, Masanori Takamatsu, Maki Shimizu, Akira Nishiyama, Hiroshi Kawachi, Shoji Kagami

TRANSLATIONAL RESEARCH   158 ( 4 )   235 - 248   2011.10

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

Excessive renin-angiotensin system (RAS) activation within the kidney induces not only renal oxidative stress but also renal scarring and dysfunction. This study examined the effects of an angiotensin II (Ang II) type I receptor (AT1R) blocker (ARB) on the progression of renal injury in rat anti-glomerular basement membrane glomerulonephritis (GN), with a particular focus on the participation of glomerular RAS activation in glomerular structural alterations, inflammation, and oxidative stress. Nephritic rats were divided into 2 groups and treated with vehicle or ARB until day 28. Treatment with ARB improved proteinuria significantly in nephritic rats. Vehicle-treated nephritic rats developed crescentic GN accompanied by marked macrophage infiltration and the enhanced expression of glomerular alpha-smooth muscle actin (alpha-SMA), angiotensinogen (AGT), Ang II, AT1R, and NADPH oxidase (Nox2) on days 7 and 28 of GN. ARB improved pathologic alterations such as crescent formation and glomerulosclerosis, and it had a significant inhibitory effect on the levels of these parameters on day 28 of GN. Enhanced superoxide production in nephritic glomeruli was decreased also by ARB. Moreover, Ang II and transforming growth factor beta (TGF-beta) in the supernatant of cultured glomeruli was increased significantly in vehicle-treated nephritic rats whereas ARB inhibited the production of these compounds significantly on day 28. These results indicate that increased glomerular RAS activity and the resulting Ang II play important roles in progressive glomerular injury-the induction of oxidative stress and TGF-beta expression, and they suggest that AT1R blockade attenuates proteinuria and progressive glomerular remodeling via the suppression of glomerular RAS activation in GN. (Translational Research 2011;158:235-248)

DOI： 10.1016/j.trsl.2011.05.003

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Curcumin ameliorates macrophage infiltration by inhibiting NF-kappa B activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy

Vivian Soetikno, Flori R. Sari, Punniyakoti T. Veeraveedu, Rajarajan A. Thandavarayan, Meilei Harima, Vijayakumar Sukumaran, Arun Prasath Lakshmanan, Kenji Suzuki, Hiroshi Kawachi, Kenichi Watanabe

NUTRITION & METABOLISM   8 ( 1 )   35 - 35   2011.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN) and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti-inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ)-induced diabetic rats.
Methods: Diabetes was induced with STZ (55 mg/kg) by intraperitoneal injection in rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic, and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 weeks. The rats were sacrificed 11 weeks after induction of diabetes. The excised kidney was used to assess macrophage infiltration and expression of various inflammatory markers.
Results: At 11 weeks after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked reduction in the body weight. All of these abnormalities were significantly reversed by curcumin. Hyperglycemia induced the degradation of I kappa Ba and NF-kappa B activation and as a result increased infiltration of macrophages (52%) as well as increased proinflammatory cytokines: TNF-alpha and IL-1 beta. Curcumin treatment significantly reduced macrophage infiltration in the kidneys of diabetic rats, suppressed the expression of above proinflammatory cytokines and degradation of I kappa Ba. In addition, curcumin treatment also markedly decreased ICAM-1, MCP-1 and TGF-beta 1 protein expression. Moreover, at nuclear level curcumin inhibited the NF-kappa B activity.
Conclusion: Our results suggested that curcumin treatment protect against the development of DN in rats by reducing macrophage infiltration through the inhibition of NF-kappa B activation in STZ-induced diabetic rats.

DOI： 10.1186/1743-7075-8-35

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