Yukinari Masuda

Nippon Medical School, Tokyo, Tokyo-to, Japan

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Publications (57)144.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The glomerulus contains well-developed capillaries, which are at risk of injury due to high hydrostatic pressure, hyperfiltration, hypertension and inflammation. However, the pathological alterations of the injured glomerular basement membrane (GBM), the main component of the glomerular filtration barrier, are still uncertain in cases of glomerulonephritis.
    Clinical and Experimental Nephrology 07/2014; · 1.25 Impact Factor
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    ABSTRACT: Hepatic artery (HA) reconstruction is performed in the clinical liver transplantation. We assessed the importance of HA reconstruction in the success of liver transplantation. Orthotopic liver transplantation was performed without immunosspression from Lewis (RT1l) to Lewis rats (syngeneic transplantation) as well as Lewis to BN (RT1n) rats (allogeneic transplantation) with or without HA reconstruction. We examined graft function, pathology, and mRNA levels using DNA arrays in both arterialized and nonarterialized liver grafts. In Lewis-to-Lewis syngeneic grafts, both the arterialized and nonarterialized grafts survived >120 days with normal graft function. lnfiltration of CD3(+) T cells and CD68(+) macrophages, marked bile duct proliferation with apoptotic epithelial cells, and expansion and increasing fibrosis of portal areas were evident in the nonarterialized grafts at day 120, although preservation of architecture was noted in the arterialized grafts. DNA array analysis of nonarterialized syngeneic grafts demonstrated the upregulation of mRNA of cell death-related proteins, cell cycle-related proteins, and inflammation-related proteins than those in arterialized grafts. Moreover, the arterialized Lewis-to-BN allogeneic grafts could survive for a long time with less severe graft dysfunction than those in non-arterialized allogeneic grafts. HA reconstruction in liver transplantation inhibited hypoxic injury and subsequent inflammation and bile duct proliferation, prevented the augmentation of T-cell-and antibody-mediated rejection, and mediated long-term graft acceptance. HA reconstruction is essential factor in the success of liver transplantation.
    Transplantation Proceedings 06/2013; 45(5):1748-53. · 0.95 Impact Factor
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    ABSTRACT: The category of chronic antibody-mediated rejection (AMR) is not included in Banff schema for liver allograft rejection. In the present study, we examined the pathology of chronic rejection using rat liver transplantation. Orthotopic liver transplantation from Lewis to BN rats was performed without immunosuppression, and with or without HA reconstruction. We studied grafts at day 120 for arterialized and day 39 for nonarterialized transplants focusing on the immunoglobulin G (IgG) deposition and the pathologic characteristics of rejection. About 20% of arterialized grafts survived more than 120 days. Between day 7 and day 120, T-cell infiltration to arterialized grafts was accompanied by IgG deposition in portal veins, hepatic arteries, and bile ducts in portal areas, sinusoids and hepatocytes. At day 120, arterialized grafts were morphologically characterized by late chronic rejection with IgG deposition, intraluminal portal veins fibrosis, intimal fibrous thickening of hepatic arteries, diffuse sinusoidal fibrosis, as well as injury and loss of bile ducts due to fibrosis. The severities of T cell-mediated rejection and AMR were higher in nonarterialized than arterialized grafts. Nonarterialized Lewis liver grafts in BN rats were rejected by day 39, as characterized by late chronic rejection with IgG deposition and cellular infiltration. In conclusion, chronic AMR may be involved in chronic rejection of liver transplantations. When chronic AMR was involved in chronic liver graft rejection, typical late morphological changes emerged within a short period.
    Transplantation Proceedings 06/2013; 45(5):1743-7. · 0.95 Impact Factor
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    ABSTRACT: Background/Aims: Acute kidney injury (AKI) is a common complication in advanced liver dysfunction. Our aim is to clarify the mechanisms of acute hepatic failure (AHF)-associated AKI. Methods: We examined the mechanisms of AHF-associated AKI, which is characterized by AKI in AHF and hyperbilirubinemia, following DA-to-Lewis rat liver transplantation. Results: During the progression of AHF and hyperbilirubinemia in liver graft rejection, AHF-associated AKI gradually developed by day 11. Degeneration and apoptotic cells were apparent in tubular epithelial cells with bile pigment accumulation and mitochondrial degeneration. Injury of peritubular capillaries (PTCs) was also noted with apoptotic endothelial cells, decreased expression of endothelial nitric oxide synthase, accumulation of α-smooth muscle actin+ pericytes and/or myofibroblasts, and inflammation. Angiogenic factors including vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in the cortex were decreased on day 11. In addition, a marked reduction in the velocity of red blood cells in PTCs was evident in vivo. Conclusions: AHF-associated AKI seems to be mediated by renal tubular epithelial cell injury with bile pigment accumulation, impaired microcirculation caused by PTC endothelial cell injury with depletion of endothelial nitric oxide synthase and angiogenic factors, and by a decrease in RBC velocity and renal inflammation. Multiple mechanisms including tubular and PTC injuries and renal inflammation may be involved in the development of AHF-associated AKI.
    American Journal of Nephrology 03/2013; 37(4):378-388. · 2.62 Impact Factor
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    ABSTRACT: Background/Aims: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. Methods: AKI was induced in MMP-2 wild-type (MMP-2(+/+)) and MMP-2-deficient (MMP-2(-/-)) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2(+/+) mice were also treated with MMP-2/MMP-9 inhibitor. Results: In both MMP-2(+/+) and MMP-2(-/-) mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2(+/+) mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2(-/-) mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2(+/+) mice. Conclusion: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.
    Nephron Experimental Nephrology 03/2013; 122(1-2):23-35. · 2.01 Impact Factor
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    ABSTRACT: We clarified the effects of an ophthalmic solution of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist on corneal inflammation and wound healing after alkali burn injury in rats. After alkali exposure, either an ophthalmic solution with 0.1% pioglitazone hydrochloride (the PPARγ group) or vehicle (the vehicle group) was topically applied to the cornea until day 14. Histological, immunohistochemical, and real-time reverse transcription polymerase chain reaction analysis were performed. After alkali injury, PPARγ expression increased, with the infiltration of many inflammatory cells. The infiltration of neutrophils and macrophages started from the corneal limbus within 6 h, and developed in the corneal center by day 7, with associated neovascularization. The accumulation of α-smooth muscle actin-positive myofibroblasts and the deposition of type III collagen were noted on day 14. The histological changes were suppressed significantly by treatment with the ophthalmic solution of the PPARγ agonist. In addition, the number of infiltrating M2 macrophages in the cornea was increased by PPARγ agonist treatment. In real-time reverse transcription polymerase chain reaction analysis, the messenger ribonucleic acid expression levels of interleukin-1β (IL-1β), IL-6, IL-8, monocyte chemoattractant protein-1, tumor necrosis factor-α, transforming growth factor beta 1, and vascular endothelial growth factor-A were decreased in the PPARγ group compared to the vehicle group in the early periods of corneal inflammation. The ophthalmic solution of the PPARγ agonist inhibited inflammation, decreased the fibrotic reaction, and prevented neovascularization in the cornea from the early phase after alkali burn injury. The ophthalmic solution of the PPARγ agonist may provide a new treatment strategy with useful clinical applications for corneal inflammation and wound healing.
    Molecular vision 01/2013; 19:2135-50. · 1.99 Impact Factor
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    ABSTRACT: Orthotopic liver transplantation (OLT) in rats is technically feasible and useful for the assessment of clinical liver transplantation and analysis of inflammatory liver diseases. OLT in rats was pioneered by Lee et al. in 1973 using hand-suture techniques of all vessels. This model has not been widely used due to the long operative time and technical demand. The cuff method was introduced by Kamada in 1979, and today, the Kamada technique is the one most commonly used worldwide. However, this technique does not include hepatic artery reconstruction, although this procedure is routinely performed in clinical transplantation. Nevertheless, several techniques for hepatic artery reconstruction in rat OLT have been reported recently, and our group also developed a simple splint technique from recipient right renal artery to donor celiac axis bearing the hepatic artery. In the present article, we describe the Kamada technique, as a standard surgical method for rat OLT. In addition, we also describe our splint technique for hepatic artery reconstruction. Then, we compare the features of Kamada technique and our splint technique for hepatic artery reconstruction and all other surgical techniques currently in use for rat OLT. The widespread use of the rat OLT model should help to provide full assessment of transplant immunology and the mechanism and treatment of inflammatory liver diseases.
    Journal of Nippon Medical School 01/2013; 80(1):4-15.
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    ABSTRACT: Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is a recently described disease entity, characterized by nonorganized electron-dense deposits in glomeruli and immunofluorescence findings indicating monoclonal immunoglobulin G deposits. The pathogenesis of many cases of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits remains unknown. We herein report 2 patients with parvovirus B19 infection who developed acute nephritic syndrome with hypocomplementemia (patient 1) or persistent proteinuria and congestive heart failure (patient 2); however, neither patient had detectable levels of serum monoclonal immunoglobulin G. Renal biopsy in both patients showed diffuse endocapillary proliferative glomerulonephritis with monoclonal immunoglobulin G3κ deposits, and electron microscopy showed nonorganized electron-dense deposits mainly in the subendothelial and mesangial areas. Clinical symptoms, abnormal laboratory findings, and urinary abnormalities recovered spontaneously in both cases within 4 weeks. Our 2 cases may be the first reported patients with proliferative glomerulonephritis with monoclonal immunoglobulin G deposits possibly associated with parvovirus B19 infection. Virus infection-associated immune disorders could be implicated in the pathogenesis of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits.
    Human pathology 07/2012; · 3.03 Impact Factor
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    ABSTRACT: Renal tubular cell death in ischemia-reperfusion does not follow the classical apoptosis or necrosis phenotype. We characterized the morphological and biochemical features of injured tubular epithelial cells in ischemic acute kidney injury (AKI). Ischemic AKI was induced in rats by 60 min of ischemia followed by 24 h of reperfusion. Light and electron microscopic TUNEL (LM-TUNEL and EM-TUNEL), gel electrophoresis of extracted DNA, and caspase-3 involvement were examined during the development of death. Damaged tubular epithelial cells with condensed and LM-TUNEL-positive (+) nuclei were prominent at 12 and 18 h after reperfusion with DNA 'ladder' pattern on gel electrophoresis. EM-TUNEL+ cells were characterized by nuclei with condensed and clumping chromatin, whereas the cytoplasm showed irreversible necrosis. The protein levels and activity of caspase-3 did not increase in kidneys after reperfusion. In addition, caspase inhibitor (ZVAD-fmk) failed to inhibit DNA fragmentation and prevent tubular epithelial cell death in ischemic AKI. Caspase-3-independent internucleosomal DNA fragmentation occurs in injured tubular epithelial cells undergoing irreversible necrosis in ischemic AKI. The manner of this cell death may be identical to the cell death termed apoptotic necrosis, aponecrosis, or necrapoptosis. Ischemia-reperfusion injury activates caspase-3-independent endonuclease, which in turn induces irreversible damage of tubular epithelial cells, and may contribute to the initiation and development of AKI.
    Nephron Experimental Nephrology 06/2012; 120(3):e103-13. · 2.01 Impact Factor
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    ABSTRACT: Renal fibrosis is a common finding in progressive renal diseases. Matrix metalloproteinases (MMPs) are involved in epithelial-to-mesenchymal transition (EMT). We investigated the role of MMP-2 and the effect of inhibition of MMPs on the development of renal fibrosis. Renal fibrosis was induced in MMP-2 wild-type (MMP-2⁺/⁺) mice by unilateral ureteral obstruction (UUO). Renal histopathology, EMT-associated molecules, and activity of MMP-2 and MMP-9 were examined during the development of interstitial fibrosis. UUO-renal fibrosis was also induced in MMP-2 deficient (MMP-2⁻/⁻) and MMP-2⁺/⁺ mice treated with minocycline (inhibitor of MMPs). In MMP-2⁺/⁺ mice, MMP-2 and MMP-9 were expressed in damaged tubules, and their activities increased in a time-dependent manner after UUO. Interstitial fibrosis was noted at day 14, with deposition of types III and I collagens and expression of markers of mesenchymal cells (S100A4, vimentin, α-smooth muscle actin, and heat shock protein-47) in damaged tubular epithelial cells, together with F4/80+ macrophage infiltration. Fibrotic kidneys expressed EMT-associated molecules (ILK, TGF-β1, Smad, Wnt, β-catenin, and Snail). In contrast, the kidneys of MMP-2⁻/⁻ mice and minocycline-treated MMP-2⁺/⁺ mice showed amelioration of renal fibrosis with reduced expression of markers of mesenchymal cells in tubular epithelial cells, inhibition of upregulated EMT-associated molecules, and suppression of macrophage infiltration. The results suggested that MMP-2 have a pathogenic role in renal interstitial fibrosis, possibly through the induction of EMT and macrophage infiltration. Inhibition of MMPs may be beneficial therapeutically in renal fibrosis.
    Laboratory Investigation 05/2012; 92(8):1149-60. · 3.96 Impact Factor
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    ABSTRACT: 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.
    Clinical and Experimental Nephrology 05/2012; · 1.25 Impact Factor
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    ABSTRACT: A 63-year-old man with hepatitis C virus infection was admitted to our hospital for nephrotic syndrome. Light microscopic analysis of a percutaneous renal biopsy showed thickening of the glomerular capillary walls and spike formation. Immunofluorescence revealed granular deposition of monoclonal immunoglobulin G1-lambda and C3 complement along the glomerular basement membrane. Urinary protein excretion decreased slightly after combined treatment with steroid and an immunosuppressive agent. Monoclonal immunoglobulin deposition disease with membranous feature is rare. Additional reports of such cases are needed to elucidate the mechanisms and optimal therapy for this rare entity.
    Clinical and Experimental Nephrology 01/2012; 16(3):468-72. · 1.25 Impact Factor
  • Journal of Nippon Medical School 01/2012; 79(6):496-7.
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    ABSTRACT: The category of acute antibody-mediated rejection (AMR) is not included in the Banff classification of liver transplantation pathology. We investigated the pathology of acute AMR using an orthotopic rat liver transplantation from DA-to-Lewis rats without immunosuppression. We studied liver graft samples at days 5, 7, and 9 to 11, focusing on the pathological characteristics of acute AMR. Progressive acute cellular rejection and AMR led to irreversible graft failure by day 11 ± 2. At day 5 immunoglobulin G (IgG) was deposited on endothelial cells in the portal veins and small arteries. Thereafter, at day 7 to day 11 the IgG deposition expanded on endothelial cells in portal veins and hepatic arteries, epithelial cells in bile ducts, sinusoids and hepatic cells in lobules. Light microscopic studies during the development of acute AMR showed interstitial edema in portal areas with neutrophilic infiltration. Rejecting grafts revealed congestion and/or thrombi in portal veins and hepatic arteries with neutrophil infiltration and fibrinogen deposition, severe degeneration of epithelial cells in bile ducts with periductal edema, intralobular edema, and hemorrhage with neutrophil infiltration and fibrinogen deposition, as well as hepatic cell degeneration and necrosis. In conclusion, acute AMR that developed in liver transplantation was characterized by endothelial cell injuries in microvasculature of portal veins, hepatic arteries, and sinusoids, accompanied by congestion, hemorrhage, thrombus formation, and neutophilic infiltration, as well as by bile duct and hepatic cell degeneration and necrosis.
    Transplantation Proceedings 09/2011; 43(7):2737-40. · 0.95 Impact Factor
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    ABSTRACT: Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.
    Pathology International 01/2011; 61(1):34-41. · 1.72 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2(+/+)) mice by 30, 60, 90, and 120 min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2(-/-)) mice and MMP-2(+/+) mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2(+/+) mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 h, peaked at 6 h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24 h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6 h and severity of AKI at 24 h increased depending on the duration of ischemia between 30 and 120 min. However, the kidneys of MMP-2(-/-) mice showed minimal ATI; serum creatinine 24 h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24 h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemia-reperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI.
    Laboratory Investigation 10/2010; 91(2):170-80. · 3.96 Impact Factor
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    ABSTRACT: The pathological process of glomerulonephritis (GN) includes glomerular capillary damage, and vascular endothelial growth factor (VEGF) has an important role in glomerular capillary repair in GN. We examined the effect of inhibition of glomerular capillary repair after capillary injury in GN. Experimental Thy-1 GN was induced in rats that were divided into two groups: rats that received anti-VEGF neutralizing antibody (50 μg per 100 g body weight per day) and those treated with the vehicle from day 2 to day 9. We assessed the renal function and histopathology serially until week 6. Rats of the Thy-1 GN group showed diffuse glomerular mesangiolysis with ballooning destruction of the capillary network by day 3. VEGF(164) protein levels increased in the damaged glomeruli during days 5 to 10, and endothelial-cell proliferation increased with capillary repair in the vehicle-injected group. Proliferative GN resolved subsequently with decreased mesangial hypercellularity, and recovery of most of the glomeruli to the normal structure was evident by week 6. In contrast, administration of anti-VEGF antibody significantly decreased endothelial-cell proliferation and capillary repair in glomeruli by week 2. Thereafter, glomerular mesangial-cell proliferation and activation continued with persistent infiltration of macrophages. At week 6, segmental glomerular sclerosis developed with mesangial matrix accumulation and proteinuria. Deposition of type I collagen was also noted in sclerotic lesions. We conclude that impaired capillary repair was the underlying mechanism in the prolongation of glomerular inflammation in proliferative GN and in the development of glomerular sclerosis. Capillary repair has an important role in the recovery of glomerular damage and in the resolution of proliferative GN.
    Laboratory Investigation 10/2010; 90(10):1468-81. · 3.96 Impact Factor
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    ABSTRACT: Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro- and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-gamma, tumor necrosis factor-alpha, and interleukin-12. In contrast, statin reduced the level of proteinuria, reduced infiltration of macrophages in glomeruli with suppression of monocyte chemotactic protein-1 expression, and inhibited the formation of necrotizing and crescentic lesions. The number of glomerular ED3-positive macrophages decreased with down-regulation of M1 macrophage-associated cytokines. Furthermore, statin augmented ED2-positive M2 macrophages with up-regulation of the M2 macrophage-associated chemokines and cytokines, chemokine (C-C motif) Iigand-17 and interleukin-10. Statin also increased the glomerular interleukin-10-expressing heme oxygenase-1-positive macrophages. Statin inhibited macrophage development, and suppressed ED3-positive macrophages, but augmented ED2-positive macrophages in M2-associated cytokine environment in vitro. We conclude that the anti-inflammatory effects of statin in glomerulonephritis are mediated through inhibition of macrophage infiltration as well as augmentation of anti-inflammatory macrophages.
    American Journal Of Pathology 09/2010; 177(3):1143-54. · 4.60 Impact Factor
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    ABSTRACT: Macrophages are heterogeneous immune cell populations that include classically activated and alternatively activated (M2) macrophages. We examined the anti-inflammatory effect of ANG II type 1 receptor (AT(1)R) blocker (ARB) on glomerular inflammation in a rat model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). The study focused on infiltrating CD8(+) and CD4(+) cells and macrophages, as well as the heterogeneity of intraglomerular macrophages. Wistar-Kyoto rats were treated with high-dose olmesartan (3 mg.kg(-1).day(-1)), low-dose olmesartan (0.3 mg.kg(-1).day(-1)), or vehicle (control) 7 days before induction of anti-GBM GN. Control rats showed mainly CD8(+) cells and ED1(+) macrophages, with a few CD4(+) cells infiltrating the glomeruli. Necrotizing and crescentic glomerular lesions developed by day 7 with the increase of proteinuria. AT(1)R was expressed on CD8(+) and CD4(+) cells and on ED1(+) macrophages. Low-dose ARB had no anti-inflammatory effects in anti-GBM GN. However, high-dose ARB reduced glomerular infiltration of CD8(+) cells and ED1(+) macrophages and suppressed necrotizing and crescentic lesions by days 5 to 7 (P < 0.05). In addition, high-dose ARB reduced the numbers of ED3(+)-activated macrophages, suppressed glomerular TNF-alpha and IFN-gamma production, and downregulated M1-related chemokine and cytokines (monocyte chemoattractant protein type 1, IL-6, and IL-12). High-dose ARB also enhanced ED2(+) M2 macrophages by day 7 with upregulation of glomerular IL-4 and IL-13 and augmented CCL17, IL-1 receptor antagonist, and IL-10. We concluded that high-dose ARB inhibits glomerular inflammation by increasing the numbers of M2 macrophages and upregulation of anti-inflammatory cytokines and by suppressing M1 macrophage development with downregulation of M1-related proinflammatory cytokines.
    AJP Renal Physiology 04/2010; 298(4):F870-82. · 4.42 Impact Factor
  • Nihon Ika Daigaku Igakkai Zasshi 01/2010; 6(3):140-146.

Publication Stats

1k Citations
144.87 Total Impact Points


  • 1983–2013
    • Nippon Medical School
      • • Department of Analytic Human Pathology
      • • Department of Internal Medicine
      • • Department of Pathology
      Tokyo, Tokyo-to, Japan
  • 2010
    • Iwate Medical University
      Morioka, Iwate, Japan
  • 1997
    • Tokyo Medical and Dental University
      • Department of Internal Medicine
      Edo, Tōkyō, Japan