Shuji Kondo

Publications (27)81.08 Total impact

• Article: Glomerular expression of hydrogen peroxide-inducible clone-5 in human and rat progressive mesangial proliferative glomerulonephritis.

  Kenichi Suga, Shuji Kondo, Sato Matsuura, Yukiko Kinoshita, Maki Urushihara, Shoji Kagami
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  ABSTRACT: Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor-β(1) (TGF-β(1))- and hydrogen peroxide (H(2)O(2))-inducible focal adhesion protein that may be necessary for maintaining the myofibroblastic phenotype in pathological scar formation. To investigate the involvement of Hic-5 in the pathogenesis of glomerulonephritis (GN), we examined the glomerular expression of Hic-5 in human and rat GN as well as the regulation of Hic-5 by TGF-β(1) in vitro. Immunohistochemical analyses showed that the expression of Hic-5 was increased in mesangial cells (MCs) in human mesangial proliferative GN. Hic-5 expression was significantly correlated not only with the levels of α-smooth muscle actin (α-SMA) and TGF-β(1), the accumulation of extracellular matrix, and the number of glomerular cells, but also with the urinary protein level in patients with GN. Glomerular Hic-5 expression increased in parallel with α-SMA expression in a rat model of mesangial proliferative GN. Combined therapy with an angiotensin type I receptor blocker and an antioxidant in this model improved the histology and the expression of Hic-5 and α-SMA. TGF-β(1) upregulated Hic-5 and α-SMA protein levels in human cultured MCs. Our findings suggest that Hic-5 is involved in changes in the MC phenotype to produce abnormal extracellular matrix remodeling in GN.
  Nephron Experimental Nephrology 01/2012; 120(2):e59-68. · 1.86 Impact Factor
• Source

  Available from: PubMed Central

  Article: Involvement of the intrarenal renin-angiotensin system in experimental models of glomerulonephritis.

  Maki Urushihara, Yukiko Kinoshita, Shuji Kondo, Shoji Kagami
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  ABSTRACT: The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.
  Journal of Biomedicine and Biotechnology 01/2012; 2012:601786. · 2.44 Impact Factor
• Article: 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.

  Yukiko Kinoshita, Shuji Kondo, Maki Urushihara, Kenichi Suga, Sato Matsuura, Masanori Takamatsu, Maki Shimizu, Akira Nishiyama, Hiroshi Kawachi, Shoji Kagami
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  ABSTRACT: 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 α-smooth muscle actin (α-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-β) 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-β expression, and they suggest that AT1R blockade attenuates proteinuria and progressive glomerular remodeling via the suppression of glomerular RAS activation in GN.
  Translational research : the journal of laboratory and clinical medicine. 10/2011; 158(4):235-48.
• Article: Expression of focal adhesion proteins in the developing rat kidney.

  Sato Matsuura, Shuji Kondo, Kenichi Suga, Yukiko Kinoshita, Maki Urushihara, Shoji Kagami
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  ABSTRACT: Focal adhesions play a critical role as centers that transduce signals by cell-matrix interactions and regulate fundamental processes such as proliferation, migration, and differentiation. Focal adhesion kinase (FAK), paxillin, integrin-linked kinase (ILK), and hydrogen peroxide-inducible clone-5 (Hic-5) are major proteins that contribute to these events. In this study, we investigated the expression of focal adhesion proteins in the developing rat kidney. Western blotting analysis revealed that the protein levels of FAK, p-FAK(397), paxillin, p-paxillin(118), and Hic-5 were high in embryonic kidneys, while ILK expression persisted from the embryonic to the mature stage. Immunohistochemistry revealed that FAK, p-FAK(397), paxillin, and p-paxillin(118) were strongly expressed in condensed mesenchymal cells and the ureteric bud. They were detected in elongating tubules and immature glomerular cells in the nephrogenic zone. Hic-5 was predominantly expressed in mesenchymal cells as well as immature glomerular endothelial and mesangial cells, suggesting that Hic-5 might be involved in mesenchymal cell development. ILK expression was similar to that of FAK in the developmental stages. Interestingly, ILK was strongly expressed in podocytes in mature glomeruli. ILK might play a role in epithelial cell differentiation as well as kidney growth and morphogenesis. In conclusion, the temporospatially regulated expression of focal adhesion proteins during kidney development might play a role in morphogenesis and cell differentiation.
  Journal of Histochemistry and Cytochemistry 06/2011; 59(9):864-74. · 2.72 Impact Factor
• Article: A case of a 6-year-old girl with anti-neutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis.

  Maki Shimizu, Takanori Sekiguchi, Natsuko Kishi, Aya Goji, Tomoko Takahashi, Hiroko Kozan, Zenichi Sakaguchi, Yukiko Kinoshita, Sato Matsuura, Kenichi Suga, Maki Urushihara, Shuji Kondo, Shoji Kagami, Katsuaki Ohara
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  ABSTRACT: A 6-year-old girl was admitted to our hospital with proteinuria, hematuria, skin rash and joint pain of the lower limbs. Due to rapid progression of renal insufficiency, hemodialysis and peritoneal dialysis were performed. She was diagnosed with rapidly progressive glomerulonephritis. Kidney biopsy showed severe crescent formation (50% of glomeruli) and no deposition of any immunoglobulins or complements. Serologically, anti-neutrophil cytoplasmic autoantibody (ANCA) was negative not only by ELISA against proteinase-3 and myeloperoxidase-ANCA but also by indirect immunofluorescent assay against cytoplasmic and perinuclear ANCA. Anti-glomerular basement membrane antibody was also negative. In the acute phase, proinflammatory cytokines such as soluble tumor necrosis factor receptor 1 (sTNFR1), soluble interleukin (IL)-2 receptor (sIL2R), IL-6 and chemokine IL-8 were elevated. The patient was diagnosed with ANCA-negative pauci-immune crescentic glomerulonephritis (CrGN). Intensive treatment with methylprednisolone pulse therapy, plasma exchange, and multiple drug therapy including prednisolone and cyclophosphamide resulted in histopathological improvement and complete remission of proteinuria. There was a possibility that sTNFR1, sIL2R, IL-6 and IL-8 might be involved in the initiation and progression of ANCA-negative pauci-immune CrGN, and to remove and suppress these cytokines might be an effective way to treat ANCA-negative pauci-immune CrGN.
  Clinical and Experimental Nephrology 03/2011; 15(4):596-601. · 1.37 Impact Factor
• Article: [Progress of pediatric nephrology].

  Shuji Kondo, Maki Urushihara, Shoji Kagami
  Nippon Jinzo Gakkai shi 01/2011; 53(1):10-4.
• Article: A case of dense deposit disease associated with a group A streptococcal infection without the involvement of C3NeF or complement factor H deficiency.

  Kenichi Suga, Shuji Kondo, Sato Matsuura, Yukiko Kinoshita, Etsuko Kitano, Michiyo Hatanaka, Hajime Kitamura, Yoshihiko Hidaka, Takashi Oda, Shoji Kagami
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  ABSTRACT: A 14-year-old girl presented with acute glomerulonephritis. Tests revealed hypocomplementemia and elevated Antistreptolysin-O titers, and renal biopsy revealed endocapillary and mesangial proliferative glomerulonephritis with double contours of the glomerular basement membrane (GBM). Despite methylprednisolone pulse therapy and the administration of oral prednisolone, overt proteinuria and hypocomplementemia persisted. A second renal biopsy 6 months later confirmed the initial diagnosis of dense deposit disease (DDD) based on electron-dense deposits in the GBM. C3 nephritic factor (C3NeF) and a deficiency of complement factor H (CFH) were not evident. A nephritis-associated plasmin receptor (NAPlr), nephritogenic group A streptococcal antigen, and the plasmin activity by in situ zymography were been in both the first and second biopsy specimens. The patient received combined immunomodulatory therapy with prednisolone and mizoribine, and the urinary protein decreased to a mild level at 27 months after disease onset. These findings suggest that persistent glomerular NAPlr deposition may be associated with the pathogenesis of DDD in some patients without the involvement of C3NeF or CFH mutation and that DDD patients of this type may respond to immunomodulatory treatment.
  Pediatric Nephrology 03/2010; 25(8):1547-50. · 2.52 Impact Factor
• Article: Urinary angiotensinogen accurately reflects intrarenal Renin-Angiotensin system activity.

  Maki Urushihara, Shuji Kondo, Shoji Kagami, Hiroyuki Kobori
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  ABSTRACT: We recently reported that immunoreactivity of intrarenal angiotensinogen (AGT) is significantly increased in IgA nephropathy patients. Meanwhile, we have developed direct enzyme-linked immunosorbent assays to measure plasma and urinary AGT (UAGT) in humans. This study was performed to test the hypothesis that UAGT levels are increased in chronic glomerulonephritis patients. We analyzed 100 urine samples from 70 chronic glomerulonephritis patients (26 from IgA nephropathy, 24 from purpura nephritis, 8 from lupus nephritis, 7 from focal segmental glomerulosclerosis, and 5 from non-IgA mesangial proliferative glomerulonephritis) and 30 normal control subjects. UAGT-creatinine ratio (UAGT/UCre) was correlated positively with diastolic blood pressure (p = 0.0326), urinary albumin-creatinine ratio (p < 0.0001), urinary protein-creatinine ratio (p < 0.0001) and urinary occult blood (p = 0.0094). UAGT/UCre was significantly increased in chronic glomerulonephritis patients not treated with renin-angiotensin system (RAS) blockers compared with control subjects (p < 0.0001). Importantly, glomerulonephritis patients treated with RAS blockers had a marked attenuation of this augmentation (p = 0.0021). These data indicate that UAGT are increased in chronic glomerulonephritis patients and treatment with RAS blockers suppressed UAGT. The efficacy of RAS blockade to reduce the intrarenal RAS activity can be confirmed by measurement of UAGT in chronic glomerulonephritis patients.
  American Journal of Nephrology 02/2010; 31(4):318-25. · 2.54 Impact Factor
• Article: ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive glomerulonephritis.

  Maki Urushihara, Masanori Takamatsu, Maki Shimizu, Shuji Kondo, Yukiko Kinoshita, Kenichi Suga, Akiko Kitamura, Sato Matsuura, Masanori Yoshizumi, Toshiaki Tamaki, Hiroshi Kawachi, Shoji Kagami
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  ABSTRACT: 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.
  AJP Renal Physiology 10/2009; 298(1):F167-76. · 4.42 Impact Factor
• Article: Low-density lipoprotein apheresis in a pediatric patient with refractory nephrotic syndrome due to focal segmental glomerulosclerosis.

  Jun Oto, Kenichi Suga, Sato Matsuura, Shuji Kondo, Yoshiaki Ohnishi, Daisuke Inui, Hideaki Imanaka, Shoji Kagami, Masaji Nishimura
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  ABSTRACT: Focal segmental glomerulosclerosis (FSGS) often leads to refractory nephrotic syndrome (NS). A high level of low-density lipoprotein (LDL) is a risk factor for the progression of NS. An 8-year-old girl presented with severe proteinuria refractory to steroid therapy. She was diagnosed with non-IgA diffuse mesangial proliferative glomerulonephritis. Oral prednisolone, methylprednisolone (mPL) pulse therapy, and cyclosporine and cyclophosphamide therapy failed to achieve remission. Follow-up renal biopsy revealed FSGS. Her serum level of LDL was high, and LDL-apheresis (LDL-A) was performed five times, followed by mPL pulse therapy. Urinary protein decreased from 2-4 g x day(-) to 0.5-1.0 g x day(-). LDL-A may be beneficial in the treatment of multidrug-resistant FSGS.
  Journal of Anesthesia 02/2009; 23(2):284-7. · 0.83 Impact Factor
• Article: Dietary doses of nitrite restore circulating nitric oxide level and improve renal injury in L-NAME-induced hypertensive rats.

  Yasuhisa Kanematsu, Kunihisa Yamaguchi, Hideki Ohnishi, Yuki Motobayashi, Keisuke Ishizawa, Yuki Izawa, Kazuyoshi Kawazoe, Shuji Kondo, Shoji Kagami, Shuhei Tomita, Koichiro Tsuchiya, Toshiaki Tamaki
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  ABSTRACT: We have reported that pharmacological doses of oral nitrite increase circulating nitric oxide (NO) and exert hypotensive effects in Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. In this study, we examined the effect of a chronic dietary dose of nitrite on the hypertension and renal damage induced by chronic L-NAME administration in rats. The animals were administered tap water containing L-NAME (1 g/l) or L-NAME + nitrite (low dose: 0.1 mg/l, medium dose: 1 mg/l, high dose: 10 mg/l) for 8 wk. We evaluated blood NO levels as hemoglobin-NO adducts (iron-nitrosyl-hemoglobin), using an electron paramagnetic resonance method. Chronic administration of L-NAME for 8 wk induced hypertension and renal injury and reduced the blood iron-nitrosyl-hemoglobin level (control 38.8 +/- 8.9 vs. L-NAME 6.0 +/- 3.1 arbitrary units). Coadministration of a low dose of nitrite with L-NAME did not change the reduced iron-nitrosyl-hemoglobin signal and did not improve the L-NAME-induced renal injury. The blood iron-nitrosyl-hemoglobin signals of the medium dose and high dose of nitrite were significantly higher than that of L-NAME alone. Chronic administration of a medium dose of nitrite attenuated L-NAME-induced renal histological changes and proteinuria. A high dose of nitrite also attenuated L-NAME-induced renal injury. These findings suggest that dietary doses of nitrite that protect the kidney are associated with significant increase in iron-nitrosyl-hemoglobin levels. We conclude that dietary nitrite-derived NO generation may serve as a backup system when the nitric oxide synthase/L-arginine-dependent NO generation system is compromised.
  American journal of physiology. Renal physiology 09/2008; 295(5):F1457-62. · 3.68 Impact Factor
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  Available from: PubMed Central

  Article: Glomerular angiotensinogen protein is enhanced in pediatric IgA nephropathy.

  Masanori Takamatsu, Maki Urushihara, Shuji Kondo, Maki Shimizu, Tetsuo Morioka, Takashi Oite, Hiroyuki Kobori, Shoji Kagami
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  ABSTRACT: Enhanced intrarenal renin-angiotensin system (RAS) is implicated in the development and progression of renal injury. To investigate whether angiotensinogen (AGT) expression is involved in glomerular RAS activity and glomerular injury, we examined glomerular AGT expression and its correlation with expression of other RAS components, and levels of glomerular injury in samples from patients with immunoglobulin A nephropathy (IgAN) (23) and minor glomerular abnormalities (MGA) (8). Immunohistochemistry showed that AGT protein was highly expressed by glomerular endothelial cells (GEC) and mesangial cells in nephritic glomeruli of IgAN compared with glomeruli of MGA. Levels of glomerular AGT protein were well correlated with levels of glomerular angiotensin II (ang II), transforming growth factor-beta (TGF-beta), alpha-smooth-muscle actin, glomerular cell number, and glomerulosclerosis score but not with those of glomerular angiotensin-converting enzyme and ang II type 1 receptor. Real-time polymerase chain reaction (RT-PCR) and Western blot analyses using cultured human GEC indicated that ang II upregulated AGT messenger ribonucleic acid (mRNA) and protein expression in a dose- and time-dependent manner. These data suggest that activated glomerular AGT expression is likely involved in elevated local ang II production and, thereby, may contribute to increased TGF-beta production and development of glomerular injury in IgAN. Augmentation of GEC-AGT production with ang II stimulation might drive further glomerular injury in a positive-feedback loop.
  Pediatric Nephrology 09/2008; 23(8):1257-67. · 2.52 Impact Factor
• Article: Big mitogen-activated protein kinase 1 (BMK1)/extracellular signal regulated kinase 5 (ERK5) is involved in platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell migration.

  Yuki Izawa, Masanori Yoshizumi, Keisuke Ishizawa, Yoshiko Fujita, Shuji Kondo, Shoji Kagami, Kazuyoshi Kawazoe, Koichiro Tsuchiya, Shuhei Tomita, Toshiaki Tamaki
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  ABSTRACT: Big mitogen-activated protein kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a newly identified member of the mitogen-activated protein (MAP) kinase family. Recently, several studies have suggested that BMK1 plays an important role in the pathogenesis of cardiovascular disease. To clarify the pathophysiological significance of BMK1 in the process of vascular remodeling, we explored the molecular mechanisms of BMK1 activation in vascular smooth muscle cells (VSMCs). From the results of co-immunoprecipitation and immunoblotting analyses, it was found that platelet-derived growth factor (PDGF), a known potent mitogen, activated BMK1 and triggered the Gab1-SHP-2 interaction in rat aortic smooth muscle cells (RASMCs). The abrogation of SHP-2 phosphatase activity by transfection of the SHP-2-C/S mutant suppressed PDGF-stimulated BMK1 activation. Infection with an adenoviral vector expressing dominant-negative MEK5alpha, which can suppress PDGF-stimulated BMK1 activation to the control level, inhibited PDGF-induced RASMC migration. Moreover, we observed an increase of BMK1 activation in injured mouse femoral arteries. From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1-SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling.
  Hypertension Research 12/2007; 30(11):1107-17. · 2.58 Impact Factor
• Article: Role of integrin-linked kinase in epithelial-mesenchymal transition in crescent formation of experimental glomerulonephritis.

  Maki Shimizu, Shuji Kondo, Maki Urushihara, Masanori Takamatsu, Katsuyoshi Kanemoto, Michio Nagata, Shoji Kagami
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  ABSTRACT: Glomerular parietal epithelial-mesenchymal transition (EMT) is a key event in crescent formation of glomerulonephritis (GN). Integrin-linked kinase (ILK) is an integrin cytoplasmic-binding protein that has been implicated in the regulation of cell adhesion, extracellular matrix organization and EMT. Transforming growth factor-beta (TGF-beta) is involved in the induction and progression of EMT in several tissues. To investigate whether ILK is involved in the crescent formation in GN, we studied the expression of ILK protein and activity in crescentic GN induced in Wistar Kyoto (WKY) rats. In addition, we investigated whether transforming growth factor-beta1 (TGF-beta1) could induce glomerular EMT and ILK by using cultured parietal epithelial cell (PEC). The expression of ILK was strongly induced in cellular crescents at day 7 and followed by a decrease in fibrocellular crescents at day 28. ILK-expressing cells in cellular crescents were double-positive for protein gene product 9.5 (PEC marker), alpha-smooth muscle actin (alpha-SMA, myofibroblasts marker) and TGF-beta1, indicating a possible contribution of ILK and TGF-beta1 to EMT in crescent formation in GN. Consistent with the finding of histological ILK expression in crescents, western blot and kinase activity assay showed an increase in both ILK protein and activity, peaking at day 7 of GN (3.7- and 3.5-fold of control, respectively). The expression of ILK increased to 3.1-fold of control when EMT was induced in cultured PEC by TGF-beta1. The present results provide the first evidence that expression and activity of ILK are increased in cellular crescents of experimental GN. Enhanced expression and activity of ILK, possibly by TGF-beta1, is associated with the induction of EMT by PEC and thereby, may participate in the formation of cellular crescents in GN.
  Nephrology Dialysis Transplantation 10/2006; 21(9):2380-90. · 3.40 Impact Factor
• Article: Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat.

  Shuji Kondo, Maki Shimizu, Maki Urushihara, Koichiro Tsuchiya, Masanori Yoshizumi, Toshiaki Tamaki, Akira Nishiyama, Hiroshi Kawachi, Fujio Shimizu, Mark T Quinn, David J Lambeth, Shoji Kagami
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  ABSTRACT: Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.
  Journal of the American Society of Nephrology 04/2006; 17(3):783-94. · 9.66 Impact Factor
• Article: Up-regulation of integrin-linked kinase activity in rat mesangioproliferative glomerulonephritis.

  Shoji Kagami, Maki Shimizu, Shuji Kondo, Akiko Kitamura, Maki Urushihara, Masanori Takamatsu, Satoshi Yamaji, Yoshiaki Ishigatsubo, Hiroshi Kawachi, Fujio Shimizu
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  ABSTRACT: This study investigated whether integrin-linked kinase (ILK) is involved in the pathogenesis of chronic glomerulonephritis (GN) by analyzing the expression and activity of glomerular ILK in a chronic rat model of mesangioproliferative GN. Double immunostaining of kidneys obtained at different time points with glomerular cell-specific markers revealed that ILK was primarily expressed by glomerular epithelial cells, and weakly by mesangial cells (MCs) and endothelial cells in control rats, but dramatically increased in a typical mesangial pattern at days 21 and 28 of GN. Semiquantitative assessment indicated that the level of glomerular ILK expression closely parallels the level of accumulation of glomerular extracellular matrix (ECM) as well as fibronectin (FN). Immunoprecipitation and kinase activity assays using isolated nephritic glomeruli indicated a striking increase of ILK activity on days 21 and 28 of GN. Further, cultured rat MCs overexpressing kinase-deficient ILK diminished FN assembly and collagen matrix remodeling as compared with control transfectants. The results showed that glomerular ILK expression and activity are markedly increased in an experimental model of chronic GN. Increased activity of ILK in MCs may contribute to the development of chronic mesangial alterations leading to glomerular scarring.
  Life Sciences 04/2006; 78(16):1794-800. · 2.53 Impact Factor
• Article: [Membranoproliferative glomerulonephritis].

  Shuji Kondo, Shoji Kagami
  Nippon rinsho. Japanese journal of clinical medicine 06/2005; 63 Suppl 5:526-9.
• Article: Nitrite is an alternative source of NO in vivo.

  Koichiro Tsuchiya, Yasuhisa Kanematsu, Masanori Yoshizumi, Hideki Ohnishi, Kazuyoshi Kirima, Yuki Izawa, Michiyo Shikishima, Tatsuhiro Ishida, Shuji Kondo, Shoji Kagami, Yoshiharu Takiguchi, Toshiaki Tamaki
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  ABSTRACT: In this study, we investigated whether orally administered nitrite is changed to NO and whether nitrite attenuates hypertension in a dose-dependent manner. We utilized a stable isotope of [15N]nitrite (15NO2-) as a source of nitrite to distinguish between endogenous nitrite and that exogenously administered and measured hemoglobin (Hb)-NO as an index of circulating NO in whole blood using electron paramagnetic resonance (EPR) spectroscopy. When 1 mg/kg Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (A(Z) = 23.4 gauss) appeared in the blood. The peak blood HbNO concentration occurred at the first measurement after intake (5 min) for treatment with 1 and 3 mg/kg (HbNO: 4.93 +/- 0.52 and 10.58 +/- 0.40 microM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 +/- 9.23 microM). In addition, coadministration of nitrite (100 mg/l drinking water) with N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 g/l) for 3 wk significantly attenuated the L-NAME-induced hypertension (149 +/- 10 mmHg) compared with L-NAME alone (170 +/- 13 mmHg). Furthermore, this phenomenon was associated with an increase in circulating HbNO. Our findings clearly indicate that orally ingested nitrite can be an alternative to L-arginine as a source of NO in vivo and may explain, at least in part, the mechanism of the nitrite/nitrate-rich Dietary Approaches to Stop Hypertension diet-induced hypotensive effects.
  AJP Heart and Circulatory Physiology 06/2005; 288(5):H2163-70. · 3.71 Impact Factor
• Article: Transforming growth factor-beta1 stimulates collagen matrix remodeling through increased adhesive and contractive potential by human renal fibroblasts.

  Shuji Kondo, Shoji Kagami, Maki Urushihara, Akiko Kitamura, Maki Shimizu, Frank Strutz, Gerhard A Müller, Yasuhiro Kuroda
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  ABSTRACT: Renal tubulointerstitial fibrosis is the common final pathway leading to end-stage renal failure. Tubulointerstitial fibrosis is characterized by fibroblast proliferation and excessive matrix accumulation. Transforming growth factor-beta1 (TGF-beta1) has been implicated in the development of renal fibrosis accompanied by alpha-smooth muscle actin (alpha-SMA) expression in renal fibroblasts. To investigate the molecular and cellular mechanisms involved in tubulointerstitial fibrosis, we examined the effect of TGF-beta1 on collagen type I (collagen) gel contraction, an in vitro model of scar collagen remodeling. TGF-beta1 enhanced collagen gel contraction by human renal fibroblasts in a dose- and time-dependent manner. Function-blocking anti-alpha1 or anti-alpha2 integrin subunit antibodies significantly suppressed TGF-beta1-stimulated collagen gel contraction. Scanning electron microscopy showed that TGF-beta1 enhanced the formation of the collagen fibrils by cell attachment to collagen via alpha1beta1 and alpha2beta1 integrins. Flow cytometry and cell adhesion analyses revealed that the stimulation of renal fibroblasts with TGF-beta1 enhanced cell adhesion to collagen via the increased expression of alpha1 and alpha2 integrin subunits within collagen gels. Fibroblast migration to collagen was not up-regulated by TGF-beta1. Furthermore, TGF-beta1 increased the expression of a putative contractile protein, alpha-SMA, by human renal fibroblasts in collagen gels. These results suggest that TGF-beta1 stimulates fibroblast-collagen matrix remodeling by increasing both integrin-mediated cell attachment to collagen and alpha-SMA expression, thereby contributing to pathological tubulointerstitial collagen matrix reorganization in renal fibrosis.
  Biochimica et Biophysica Acta 09/2004; 1693(2):91-100. · 4.66 Impact Factor
• Article: Transforming growth factor-beta in renal disease with glycogen storage disease I.

  Maki Urushihara, Shoji Kagami, Michinori Ito, Koji Yasutomo, Shuji Kondo, Akiko Kitamura, Akiyoshi Takahashi, Yasuhiro Kuroda
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  ABSTRACT: We report a 14-year-old patient with Japanese glycogen storage disease I (GSD-I) who was found to have proteinuria. Renal biopsy revealed massive tubular atrophy and interstitial fibrosis with mononuclear cell infiltration, but the glomeruli were almost normal. The epithelial cells of tubules contained periodic acid-Schiff-positive glycogen deposits digested by diastase. In an immunohistological study, transforming growth factor (TGF)-beta expression was increased in tubular epithelial cells compared with a normal control kidney specimen. These data suggest that increased TGF-beta expression is involved in the pathophysiology of renal interstitial fibrosis in a patient with GSD-I.
  Pediatric Nephrology 07/2004; 19(6):676-8. · 2.52 Impact Factor