Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

2009 ◽  
Vol 297 (3) ◽  
pp. F679-F684 ◽  
Author(s):  
Mari Tomiyama-Hanayama ◽  
Hiromi Rakugi ◽  
Masaharu Kohara ◽  
Toru Mima ◽  
Yasuo Adachi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Apolipoprotein E ◽  
Interleukin 6 ◽  
Renal Injury ◽  
Mesangial Cell ◽  
Organ Damage ◽  
Glomerular Injury ◽  
Mesangial Cell Proliferation ◽  
Matrix Expansion ◽  
Interleukin 6 Receptor

Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE−/−) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE−/− mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage.

Bradykinin induces tubulin phosphorylation and nuclear translocation of MAP kinase in mesangial cells

1997 ◽  
Vol 273 (6) ◽  
pp. F916-F924 ◽  
Author(s):  
Ayad A. Jaffa ◽  
Bradley S. Miller ◽  
Steven A. Rosenzweig ◽  
Padma S. Naidu ◽  
Victoria Velarde ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mesangial Cell ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Injury ◽  
Mesangial Cell Proliferation ◽  
Mitogen Activated Protein ◽  
Matrix Expansion ◽  
Dose Dependent Increase

Glomerular hypertension and glomerular hypertrophy act early and synergistically to promote glomerular injury in diabetes. We have previously shown that increased renal kinin production contributes to the glomerular hemodynamic abnormalities associated with diabetes. Glomerulosclerosis, characterized by mesangial cell proliferation and matrix expansion, is the final pathway leading to renal failure. The signal(s) initiating mesangial cell proliferation is ill defined. In the present study, we utilized immunofluorescence, immunoprecipitation, and immunoblotting techniques to identify substrates that are tyrosine phosphorylated in response to bradykinin action in mesangial cells. Immunofluorescence microscopy of mesangial cells stained with anti-phosphotyrosine (anti-PY) antibodies following bradykinin treatment (10−9–10−6M) revealed a dose-dependent increase in the labeling of cytoplasmic and nuclear proteins. Immunoprecipitation with anti-PY, followed by immunoblot revealed bradykinin-induced tyrosyl phosphorylation of tubulin and mitogen-activated protein kinase (MAPK). Confocal microscopy of mesangial cells stained for MAPK indicated that bradykinin stimulation resulted in translocation of MAPK from the cytoplasm to the nucleus by 2 h. These data demonstrate that bradykinin action results in the tyrosine phosphorylation of cellular proteins in mesangial cells and suggest a role for tubulin and MAPK in the signaling cascade of bradykinin leading to altered mesangial function.

Apolipoprotein E Regulates Primary Cultured Human Mesangial Cell Proliferation

2006 ◽  
Vol 102 (2) ◽  
pp. e62-e70 ◽  
Author(s):  
Yixiang Zhang ◽  
Yuichiro Yasumoto ◽  
Toru Ikeda ◽  
Syozo Takenouchi ◽  
Atsushi Sogabe ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Apolipoprotein E ◽  
Mesangial Cell ◽  
Human Mesangial Cell ◽  
Mesangial Cell Proliferation

scholarly journals Simvastatin suppresses glomerular cell proliferation and macrophage infiltration in rats with mesangial proliferative nephritis.

1998 ◽  
Vol 9 (11) ◽  
pp. 2027-2039
Author(s):  
A Yoshimura ◽  
K Inui ◽  
T Nemoto ◽  
S Uda ◽  
Y Sugenoya ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Coenzyme A ◽  
Mesangial Cell ◽  
Glomerular Cell ◽  
Simvastatin Treatment ◽  
Macrophage Recruitment ◽  
Mesangial Cell Proliferation ◽  
Matrix Expansion ◽  
Disease Induction ◽  
Coenzyme A Reductase

Inhibition of 3-hydro-3-methylglutaryl coenzyme A reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types. Therefore, 3-hydro-3-methylglutaryl coenzyme A reductase inhibitors may have a beneficial effect in glomerular disease, because glomerular cell proliferation is a central feature in the active glomerular injury. This study examines the effect of simvastatin on glomerular pathology in a rat mesangial proliferative glomerulonephritis (GN) induced by anti-thymocyte antibody (anti-Thy 1.1 GN). There was no difference in the degree of the antibody and complement-mediated initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation. The proliferative activity was maximal at day 4 after disease induction (26.5+/-7.0 of proliferating cell nuclear antigen-positive cells/glomerulus); however, approximately 70% of proliferation was suppressed by simvastatin treatment. At day 4 after disease induction, simvastatin administration also decreased alpha-smooth muscle actin expression in the glomerulus, which is a marker for mesangial cell activation. Inhibition of monocyte/macrophage recruitment into glomeruli by simvastatin was also a prominent feature. There was a 30% decrease in the number of glomerular ED-1+ cells by simvastatin treatment at day 2 after disease induction. Furthermore, simvastatin remarkably suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. We also found that the platelet-derived growth factor expression was reduced in simvastatin-treated nephritic rats, which might simply reflect the reduction in mesangial cell proliferation and mesangial cellularity. There was no significant difference in plasma cholesterol or triglyceride levels between simvastatin- and vehicle-treated nephritic rats at day 2 and day 4, which corresponded to the times when simvastatin treatment resulted in a reduction in mesangial cell proliferation. In conclusion, this is the first report to find that mesangial cell proliferation and matrix expansion have been blocked by simvastatin in vivo. The protective effect of simvastatin in the matrix expansion in anti-Thy1.1 GN was partly by inhibition of mesangial cell proliferation and monocyte/ macrophage recruitment into glomeruli, which were independent of a change in circulating lipids.

scholarly journals Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo

1997 ◽  
Vol 51 (1) ◽  
pp. 69-78 ◽  
Author(s):  
Frank Eitner ◽  
Ralf Westerhuis ◽  
Michael Burg ◽  
Birgit Weinhold ◽  
Hermann-Josef Gröne ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Interleukin 6 ◽  
Mesangial Cell ◽  
Mesangial Cell Proliferation ◽  
Matrix Production

scholarly journals Increased mesangial cGMP levels prevent mesangial cell proliferation and matrix expansion in experimental glomerulonephritis

2007 ◽  
Vol 7 (S1) ◽  
Author(s):  
Bernd Hohenstein ◽  
Christoph Daniel ◽  
Sandra Wittmann ◽  
Andrea Braun ◽  
Johannes-Peter Stasch ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mesangial Cell ◽  
Experimental Glomerulonephritis ◽  
Mesangial Cell Proliferation ◽  
Matrix Expansion

scholarly journals Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression.

1995 ◽  
Vol 5 (11) ◽  
pp. 1895-1902 ◽  
Author(s):  
D J Nikolic-Paterson ◽  
G H Tesch ◽  
H Y Lan ◽  
R Foti ◽  
R C Atkins
Keyword(s):  
Cell Proliferation ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Class Ii ◽  
Glomerular Injury ◽  
Histocompatibility Complex ◽  
Mesangial Cell Proliferation

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by cultured rat mesangial cells. Of particular interest was the finding that deoxyspergualin inhibited the de novo cell surface expression of MHC class II antigens after interferon-gamma stimulation. However, deoxyspergualin did not prevent the cytoplasmic accumulation of MHC class II molecules, indicating that the drug interfered with a posttranslational event in MHC class II processing and/or assembly. Deoxyspergualin was not a general inhibitor of mesangial cells, and it had no effect on constitutive or lipopolysaccharide-induced transforming growth factor beta 1 expression. In conclusion, deoxyspergualin has been shown to inhibit the mesangial cell response to glomerular injury. This novel mode of action may provide an additional therapeutic benefit in the treatment of proliferative forms of glomerulonephritis.

scholarly journals Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor.

1992 ◽  
Vol 175 (5) ◽  
pp. 1413-1416 ◽  
Author(s):  
R J Johnson ◽  
E W Raines ◽  
J Floege ◽  
A Yoshimura ◽  
P Pritzl ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Wound Repair ◽  
Mesangial Cell ◽  
Platelet Derived Growth Factor ◽  
Inflammatory Conditions ◽  
Mesangial Cell Proliferation ◽  
Matrix Expansion

Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells in culture, is expressed in vivo in a variety of inflammatory conditions associated with cell proliferation, including atherosclerosis, wound repair, pulmonary fibrosis, and glomerulonephritis. However, it is not known if PDGF mediates the fibroproliferative responses that characterize these inflammatory disorders. We administered neutralizing anti-PDGF IgG or control IgG to rats with mesangial proliferative nephritis. Inhibition of PDGF resulted in a significant reduction in mesangial cell proliferation, and largely prevented the increased deposition of extracellular matrix associated with the disease. This suggests that PDGF may have a central role in proliferative glomerular disease.

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