Yoshimi Sekiguchi
Juntendo University
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Featured researches published by Yoshimi Sekiguchi.
Kidney International | 2010
Pranali Patel; Yoshimi Sekiguchi; Kook-Hwan Oh; Sarah Patterson; Martin Kolb; Peter J. Margetts
Transition of peritoneal mesothelial cells to a mesenchymal phenotype plays an integral role in the angiogenic and fibrotic changes seen in the peritoneum of patients receiving long-term peritoneal dialysis. While signaling by transforming growth factor (TGF)-beta through Smad proteins likely causes these changes, it is possible that non-Smad pathways may also play a role. Here, we found that Smad3-deficient mice were protected from peritoneal fibrosis and angiogenesis caused by adenovirus-mediated gene transfer of active TGF-beta1 to mesothelial cells; however, mesothelial transition occurred in this setting, suggesting involvement of non-Smad mechanisms. The phosphatidyl inositol 3 kinase (PI3K) target, Akt, was upregulated in both Smad-deficient and wild-type mice after exposure to TGF-beta1. In vivo inhibition of the mammalian target of rapamycin (mTOR) by rapamycin completely abrogated the transition response in Smad3-deficient but not in wild-type mice. Rapamycin blocked nuclear localization of beta-catenin independent of glycogen synthase kinase 3beta activity. Further, in Smad3-deficient mice rapamycin reduced the expression of alpha-smooth muscle actin, which is an epithelial-to-mesenchymal transition-associated gene. Hence, we conclude that TGF-beta1 causes peritoneal injury through Smad-dependent and Smad-independent pathways; the latter involves redundant mechanisms inhibited by rapamycin, suggesting that suppression of both pathways may be necessary to abrogate mesothelial transition.
Journal of Cellular and Molecular Medicine | 2012
Yoshimi Sekiguchi; Jing Zhang; Sarah Patterson; Limin Liu; Chieko Hamada; Yasuhiko Tomino; Peter J. Margetts
Patients with end‐stage kidney disease on peritoneal dialysis often develop progressive scarring of the peritoneal tissues. This manifests as submesothelial thickening and is associated with increased vascularization that leads to ultrafiltration dysfunction. Hypoxia induces a characteristic series of responses including angiogenesis and fibrosis. We investigated the role of hypoxia in peritoneal membrane damage. An adenovirus expressing transforming growth factor (TGF) β was used to induce peritoneal fibrosis. We evaluated the effect of the mTOR inhibitor rapamycin, which has been previously shown to block hypoxia‐inducible factor (HIF) 1α. We also assessed the effect of HIF1α independently using an adenovirus expressing active HIF1α. To identify the TGFβ1‐independent effects of HIF1α, we expressed HIF1α in the peritoneum of mice lacking the TGFβ signalling molecule Smad3. We demonstrate that TGFβ‐induced fibroproliferative tissue is hypoxic. Rapamycin did not affect the early angiogenic response, but inhibited angiogenesis and submesothelial thickening 21 days after induction of fibrosis. In primary mesothelial cell culture, rapamycin had no effect on TGFβ‐induced vascular endothelial growth factor (VEGF) but did suppress hypoxia‐induced VEGF. HIF1α induced submesothelial thickening and angiogenesis in peritoneal tissue. The fibrogenic effects of HIF1α were Smad3 dependent. In summary, submesothelial hypoxia may be an important secondary factor, which augments TGFβ‐induced peritoneal injury. The hypoxic response is mediated partly through HIF1α and the mTOR inhibitor rapamycin blocks the hypoxic‐induced angiogenic effects but does not affect the direct TGFβ‐mediated fibrosis and angiogenesis.
Nephrology Dialysis Transplantation | 2010
Tetsutaro Shimaoka; Chieko Hamada; Kayo Kaneko; Hiroaki Io; Yoshimi Sekiguchi; Seiki Aruga; Jiro Inuma; Yuko Inami; Yoko Hotta; Satoshi Horikoshi; Toshio Kumasaka; Yasuhiko Tomino
BACKGROUND Morphologic changes of the peritoneum such as peritoneal fibrosis and vasculopathy develop during peritoneal dialysis (PD). In 2002, Williams et al. reported microscopic characteristics of peritoneal changes in PD patients. These studies pointed out the importance of establishing a global standard for qualitative and quantitative histological evaluations. The objectives of the present study are (i) to verify the methods for assessing peritoneal thickness and classifying vasculopathy in peritoneal specimens using the assessment of Williams et al. and (ii) to propose a simple assessment that reflects clinical features such as PD duration and peritoneal function. METHODS Parietal peritoneal samples were obtained from 35 patients that included 27 patients with PD and 8 uraemic patients without PD. In all samples, the maximum and average thicknesses of the submesothelial compact (SMC) zone were measured to assess peritoneal interstitial fibrosis using KS400 imaging analysis. Vasculopathy was also assessed by calculation of patency rates of the vascular lumens using the diameter and area, and by measurement of dimensions of vascular wall hyalinization in each vessel specimen. RESULTS The median values of maximum and average thicknesses of the SMC zone exceeded 200 μm in uraemic patients without PD treatment. There was a significant relationship between the maximum and average thicknesses of the SMC zone (P < 0.0001). Four to 30 vessels were examined in each participant. Various grades of vasculopathy were observed in each specimen. According to the predominant vasculopathy found in each vessel, the prevalence of serious vasculopathy increased with increasing PD duration. Vascular patency calculated from wall thickness was significantly related to that calculated by the area and to the thickness of hyalinization. Average vascular patency assessed from 5 to 10 vessels in each patient having diameters ranging from 10 to 40 μm was related to PD duration and to peritoneal function (D4/P). CONCLUSIONS A random-points measurement of average SMC thickness provides a descriptive evaluation of the severity of peritoneal fibrosis that minimizes artefacts during processing and avoids human error. In addition, the average patency in post-capillary venules appears to accurately reflect clinical features such as PD duration and peritoneal permeability.
Journal of Artificial Organs | 2012
Yoshimi Sekiguchi; Chieko Hamada; Yuuki Ro; Hirotaka Nakamoto; Masanori Inaba; Tetsutaro Shimaoka; Hiroaki Io; Ichiro Koyanagi; Seiki Aruga; Jiro Inuma; Kayo Kaneko; Yoko Hotta; Peter J. Margetts; Hideki Mochizuki; Satoshi Horikoshi; Yasuhiko Tomino
Marked thickening of the peritoneum and vasculopathy in the submesothelial compact zone have been reported in long-term peritoneal dialysis patients. Bone marrow (BM)-derived cell lines are considered to be useful tools for therapy of various diseases. To clarify the role of BM-derived cells in the peritoneal fibrosis (PF) model, we analyzed several lineages of cells in the peritoneum. BM cells from green fluorescent protein (GFP) transgenic mice were transplanted into naïve C57Bl/6 mice. Chlorhexidine gluconate (CG) was injected intraperitoneally to induce PF. Immunohistochemical analysis was performed with parietal peritoneum using anti-Sca-1 or -c-Kit and -GFP antibodies. Isolated BM cells were also transplanted into the CG-stimulated peritoneum. BM-derived cells from GFP transgenic mice appeared in the submesothelium from days 14 to 42. Both GFP- and stem cell marker-positive cells were observed in the submesothelium and on the surface. Isolated c-Kit-positive cells, transplanted into the peritoneal cavity, differentiated into mesothelial cells. In this study, we investigated whether or not BM-derived cells play a role in the repair of PF and immature cells have the potential of inducing repair of the peritoneum. The findings of this study suggest a new concept for therapy of PF.
Peritoneal Dialysis International | 2010
Hiroaki Io; Yuuki Ro; Yoshimi Sekiguchi; Tetsutaro Shimaoka; Jiro Inuma; Yoko Hotta; Seiki Aruga; Yuko Inami; Michiko Sato; Takashi Kobayashi; Atsumi Masuda; Kayo Kaneko; Chieko Hamada; Eiji Ohtaki; Satoshi Horikoshi; Yasuhiko Tomino
♦ Background: Echocardiography is widely used for the evaluation of cardiac structures and function. The prognostic value of assessment of left cardiac atrium (LA) size in peritoneal dialysis (PD) patients is still unclear. The objective of the present study is to investigate prospectively a longitudinal monitoring of echocardiography parameters after start of PD. We also investigated a correlation study among plasma atrial natriuretic peptide (ANP) level, LA size, and cardiac function undergoing aggressive treatment. ♦ Methods: Correlation among plasma ANP, LA size, and cardiac function was prospectively analyzed by Doppler echocardiography in 32 PD patients in Juntendo University Hospital, Tokyo. Measurement of these parameters was performed at 0, 6, 12, 18, and 24 months after start of PD. All patients were treated with an angiotensin type 1 receptor blocker to control blood pressure to less than 140/90 mmHg. Other antihypertensive drugs such as diuretics and/or calcium channel blockers were added if blood pressure rose to over 140/90 mmHg. Hemoglobin and hematocrit levels were targeted at 10.0 g/dL and 30.0% respectively with recombinant human erythropoietin treatment. A diuretic was added or patients decreased their water intake if ANP was more than 43.0 pg/mL or LA diameter (LAD) more than 39 mm, and for other basic markers of volume status. Cardiac function was measured before and after drainage of PD fluid to evaluate the influence of cardiac function. ♦ Results: LAD at start of dialysis (36 ± 4.6 mm) decreased significantly to 33 ± 3.3 mm (p < 0.05), 33 ± 3.2 mm (p < 0.05), and 33 ± 3.6 mm (p < 0.05) after 6, 12, and 24 months, respectively. Ejection fraction after 6 months was significantly increased compared with that at start of dialysis (p < 0.05). Left ventricular mass index (LVMI) after 6, 12, and 24 months was significantly decreased compared with that at start of dialysis (p < 0.05). ANP was 56 ± 39 pg/mL at start of dialysis and decreased significantly to 33 ± 19 pg/mL after 24 months (p < 0.05). ANP was significantly correlated with LAD (r = 0.412, p < 0.01), transmitral A wave flow velocity (r = 0.429, p < 0.01), and LVMI (r = 0.426, p < 0.01). Instillation of the dialysis fluid did not affect any parameters except inferior vena cava dimension. ♦ Conclusion: This study demonstrates a reduction in LA size and LVMI in PD patients followed over 24 months. Left ventricular structure, contraction, and compliance were well preserved in PD patients undergoing aggressive treatment based on measurements of plasma ANP and LAD.
Nephrology Dialysis Transplantation | 2010
Yoko Hotta; Kayo Kaneko; Jiro Inuma; Yuko Inami; Seiki Aruga; Tetsutaro Shimaoka; Yoshimi Sekiguchi; Hiroaki Io; Chieko Hamada; Masuo Obinata; Masatsugu Ueda; Yasuhiko Tomino
BACKGROUND Establishing a peritoneal mesothelial cell (MC) line in which the native characteristics of primary MCs are constantly maintained in vivo is of great significance for investigating their morphological and functional changes in peritoneal dialysis. We established transgenic (Tg) rats that expressed the temperature-sensitive tsA58 mutant of the simian virus 40 large T-antigen (tsSV40T), which served as a source of immortalized rat cell lines. The cells were immortalized at a permissive temperature of 33 degrees C, although they were differentiated at a non-permissive temperature of 38 degrees C. In this study, we established a novel MC line from tsSV40T Tg rats and evaluated its characteristics. METHODS MCs were isolated from 8-week-old tsSV40T Tg rats and cloned. MCs from 8-week-old Wistar rats were used as controls. These cells were immunohistochemically and phenotypically evaluated by immunofluorescence, phase contrast and electron microscopy. The production of plasminogen activator inhibitor 1 (PAI-1) from MCs stimulated by tumour necrosis factor-alpha (TNF-alpha) was measured. RESULTS The tsSV40T MCs showed a cobblestone-like appearance at 33 and 38 degrees C, which was similar to normal primary cultured MCs. Microvilli-like structures were observed on the cell surface by a scanning electron microscope at 33 and 38 degrees C. Wilms tumour-1 and pancytokeratin, as MC markers, were expressed at 33 and 38 degrees C. Following TNF-alpha stimulation, PAI-1 production of tsSV40T MCs was similar to that of normal primary cultured MCs. CONCLUSION We established a novel, conditionally immortalized MC line that continuously retained the characteristics of primary cultured peritoneal MCs. This cell line might be a useful tool for various types of in vitro biological research on peritoneal dialysis.
Seminars in Dialysis | 2014
Hiroaki Io; Kunimi Maeda; Yoshimi Sekiguchi; Tetsutaro Shimaoka; Seiki Aruga; Junichiro Nakata; Hirotaka Nakamoto; Yoko Hotta; Ichiro Koyanagi; Masanori Inaba; Reo Kanda; Takanori Nakano; Keiichi Wakabayashi; Yuu Sasaki; Jiro Inuma; Kayo Kaneko; Chieko Hamada; Mitsumine Fukui; Yasuhiko Tomino
Peritoneal dialysis (PD) catheters often become severely dislocated, which may lead to malfunction. With the aim of preventing this complication, we have developed a simple method of fixing the catheter downwards in the peritoneal cavity (fixation technique), a technique that does not require a laparoscope. Sixteen patients were implanted using the conventional placement technique and 25 patients were implanted using the fixation technique. The location of the catheter tip was classified from grade 1 (downward, normal) to 5 (dislocated). The frequency of dislocation (defined as the extended time and/or decrease in volume when draining the PD solution) was measured for both the fixation technique and conventional placement technique. There was a significant difference in grade between the fixation technique (2.72 ± 1.01) and conventional technique (3.92 ± 1.31). The time until first dislocation was significantly different between the fixation technique (59.3 ± 48.1 days) and conventional technique (8.8 ± 14.6 days). The time until any dislocation was significantly different between the fixation technique (69.2 ± 41.9 days) and conventional technique (12.9 ± 13.7 days). Complications were not significantly different between the fixation technique and conventional technique. The fixation technique appears to be simple, safe, and useful for preventing severe dislocation and for lengthening the time until dislocation in PD patients.
Hong Kong Journal of Nephrology | 2007
Yoshimi Sekiguchi; Michifumi Yamashita; Tomoko Sakamoto; Kyoichi Tashiro; Atsushi Kurusu; Yuichiro Makita; Kunimi Maeda; Mitsumine Fukui; Chieko Hamada; Satoshi Horikoshi; Yasuhiko Tomino
We report the clinical course and immunohistochemical analysis of a patient who presented with tubulointerstitial nephritis and uveitis syndrome (TINU syndrome). The patient, a 40-year-old woman, was referred to our hospital with general fatigue and a slight fever from another hospital. Mast cells are closely related to the development of renal interstitial fibrosis in patients with glomerulonephritis. To determine the role of mast cells in renal interstitial injury in TINU patients, we performed immunohistochemical studies on renal biopsy specimens using anti-human tryptase and anti-human chymase antibodies specific for mast cells. Double immunostaining of tryptase and chymase was also performed in renal tissues. In double immunofluorescence, cells with both chymase and tryptase (MCtc) were marked in the regions of interstitial fibrosis in this patient. It appears that mast cells are one of the constitutive cells of interstitial fibrosis in patients with TINU syndrome.
Clinical Nephrology | 2007
Kenji Yamaji; Atushi Kurusu; Okamoto M; Yoshimi Sekiguchi; Satoshi Horikoshi; Yasuhiko Tomino
Journal of Artificial Organs | 2014
Hirotaka Nakamoto; Chieko Hamada; Tetsutaro Shimaoka; Yoshimi Sekiguchi; Hiroaki Io; Kayo Kaneko; Satoshi Horikoshi; Yasuhiko Tomino