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

Eitner, Frank; Westerhuis, Ralf; Burg, M.P.M. van der; Weinhold, Birgit; Gröne, Hermann–Josef; Ostendorf, Tammo; Rüther, Ulrich; Koch, Karl-Martin; Rees, Andrew J.; Floege, Jürgen

doi:10.1038/ki.1997.9

Cited by 55 publications

(38 citation statements)

References 39 publications

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“…ApoE Inhibits Platelet-derived Growth Factor (PDGF) and LDL-stimulated Cell Proliferation-Although the trigger for mesangial proliferation is not clear, studies have identified several possible candidates including PDGF, interleukin-6, and LDL (25)(26)(27). We tested whether apoE can suppress the growth-promoting effects of these agents.…”

Section: Lack Of Apoe Results In Mesangialmentioning

confidence: 99%

A Protective Role for Kidney Apolipoprotein E

Chen¹,

Paka²,

Kako³

et al. 2001

Journal of Biological Chemistry

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Mesangial expansion is a key feature in the pathogenesis of numerous renal diseases involving the glomerulus. Studies indicate that mutations in apolipoprotein E (apoE) might independently contribute to kidney dysfunction. Although the role of apoE as an atheroprotective molecule is well established, its role in kidney is unclear. In this study, we sought to explore whether apoE has a protective function in kidney. Northern blotting and reverse transcriptase-polymerase chain reaction showed apoE expression in kidney, and mesangial cell is a major source of apoE in kidney. In the kidneys of 14 -16-month-old apoE-null mice, hematoxylin-eosin (HE) staining revealed increased mesangial cell proliferation and matrix formation compared with wild type mice or apoB-overexpressing mice, which have elevated plasma cholesterol and triglycerides. These data suggest that lack of apoE, rather than hyperlipidemia, contributes to increased mesangial expansion. We isolated mesangial cells from mouse kidney and determined the effect of apoE on cell growth. ApoE (E3, 10 g/ml) completely inhibited serum, platelet-derived growth factor (10 ng/ml), as well as low density lipoprotein-induced mesangial cell proliferation. Among the three isoforms, E3 was found to be most effective in inhibiting mesangial cell proliferation. ApoE did not show any cytotoxic effect, and moreover, inhibited mesangial cell apoptosis induced by oxidized low density lipoprotein. These data suggest that apoE regulates growth as well as survival of mesangial cells. We previously showed that apoE induces matrix heparan sulfate proteoglycan (HSPG) in vascular cells, which has an antiproliferative effect. Similarly, apoE induced the mesangial matrix HSPG. Perlecan is the major HSPG of mesangial matrix and subendothelial space, and consistent with this, blockade of perlecan reversed the antiproliferative effect of apoE. Immunohistochemistry revealed reduced staining of perlecan in kidney from apoE-null mice. Because the loss of anionic HSPG in the basement membrane and mesangial matrix is associated with disruption of filtration barrier, these data suggest a novel role for kidney apoE in preserving the filtration barrier. In summary, apoE has a protective function in kidney as an autocrine regulator of mesangial expansion and kidney function.

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Section: Lack Of Apoe Results In Mesangialmentioning

confidence: 99%

A Protective Role for Kidney Apolipoprotein E

Chen¹,

Paka²,

Kako³

et al. 2001

Journal of Biological Chemistry

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“…The major sources of IL-6 are reported to be monocytes, fibroblasts, and endothelial cells (3). IL-6 is bound as a dimer within an IL-6R␣ hexameric ligand-receptor complex (4) and can induce Ig production, T-cell maturation, as well as glomerulonephritis and plasmocytosis (5)(6)(7). SCID-IL-6 transgenic mice do not show such abnormalities (8).…”

Section: Systemic Lupus Erythematosus (Sle) Is a Complex Autoimmune Dmentioning

confidence: 99%

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Pflegerl

Vesely

Hantusch

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, we found RON in monocytes that infiltrated the glomeruli; in addition, we showed that RON is induced de novo in circulating monocytes that were stimulated in vitro with LPS. These results suggest that in anti-Thy 1 nephritis, the inflamed glomerular environment (27)(28)(29) induces RON in monocytes that circulate locally, so monocytes become responsive to MSP.…”

Section: Discussionmentioning

confidence: 78%

Neutralization of Macrophage-Stimulating Protein Ameliorates Renal Injury in Anti–Thy 1 Glomerulonephritis

Rampino

Soccio

Gregorini

et al. 2007

Journal of the American Society of Nephrology

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Macrophage-stimulating protein (MSP) is a scatter factor that causes cell proliferation and migration, and receptor origin nantaise (RON) is its receptor. RON is expressed in macrophages and mesangial cells, and MSP is produced by renal tubular cells. This study investigated whether MSP/RON participate in the pathogenesis of anti-Thy 1 nephritis, a glomerular disease that is characterized by invasion of circulating monocytes into glomeruli and migration and proliferation of mesangial cells. In vivo, renal function and histopathology were studied in rats that had anti-Thy 1 disease and were untreated and treated with a neutralizing anti-MSP antibody. In vitro, whether monocytes express RON and whether MSP has a chemotactic effect on monocytes were studied. In vivo, in anti-Thy 1 disease, MSP was expressed de novo in glomeruli, and neutralization of MSP attenuated the rise in serum creatinine and proteinuria, stopped glomerular neutrophil and monocyte influx, protected from glomerular injury, and lessened mesangial cell overgrowth. M acrophage-stimulating protein (MSP) is a "scatter factor" that is homologous to hepatocyte growth factor (HGF) (1-3). The receptor of MSP is receptor origin nantaise (RON), a proto-oncogene product (4). Information on the cell source of MSP and the biologic meaning of the MSP/RON system is very limited. Originally, MSP was described as a serum factor produced by hepatocytes that enhanced the chemotactic response of macrophages to the C5a fraction of complement (5-8). It was then demonstrated that MSP induces proliferation, migration, and invasive growth of keratinocytes and epithelial tumor cell lines. These findings have suggested a role of MSP in skin-wound healing and in oncogenesis (8 -15).We have shown that MSP is diffusely expressed in tubular epithelium of human kidney and that proximal tubular cells release MSP. In addition, we have shown that human mesangial cells express RON and that MSP induces in human mesangial cell growth, migration, invasion into an artificial collagen matrix, and synthesis of IL-6 (16). These findings suggest that MSP, either circulating or as paracrine product, may participate in the pathogenesis of mesangial proliferative glomerulonephritis (e.g., by inducing mesangial cell proliferation, movement, and invasion into the subendothelial space). An additional mechanism of glomerular endocapillary proliferation that may be induced by MSP is the recruitment of circulating monocytes into the glomerulus. In fact, MSP has a chemoattractant action on macrophages that are derived from monocytes. As yet, however, we ignore whether circulating monocytes express RON, and indeed the role of MSP in the pathogenesis of glomerulonephritis or any else inflammatory disease has never been investigated.This study was performed to understand whether the MSP/ RON system plays a pathogenic role in mesangial proliferative glomerulonephritis. We investigated MSP/RON in anti-Thy 1 glomerulonephritis because in this experimental disease, both proliferation of resident mesangial...

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

Cited by 55 publications

References 39 publications

A Protective Role for Kidney Apolipoprotein E

A Protective Role for Kidney Apolipoprotein E

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Neutralization of Macrophage-Stimulating Protein Ameliorates Renal Injury in Anti–Thy 1 Glomerulonephritis

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