Suppression Subtractive Hybridization Identifies High Glucose Levels as a Stimulus for Expression of Connective Tissue Growth Factor and Other Genes in Human Mesangial Cells

Murphy, Madeline; Godson, Catherine; Cannon, Sarah; Kato, Shinichiro; Mackenzie, Harald S.; Martin, Finian; Brady, Hugh R.

doi:10.1074/jbc.274.9.5830

Cited by 371 publications

(337 citation statements)

References 39 publications

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“…The data presented confirm the results of other investigators (Murphy et al, 1999;Keil et al, 2002;Shi-Wen et al, 2006) (A,B). SEAP activity in relative light units was measured in conditioned media after 48 h using a SEAP fluorescent assay kit as described in the materials and methods section.…”

Section: Discussionsupporting

confidence: 83%

Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

Wani

Carl²,

Henger³

et al. 2007

BCHM

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Mesangial cells are thought to be important mediators of glomerular inflammation and fibrosis. Studies have established a direct role for nitric oxide (NO) in the regulation of gene expression in mesangial cells. Representational difference analysis was used to investigate changes in gene expression elicited by the treatment of S-nitroso-L-glutathione in rat mesangial cells. Seven upregulated and 11 downregulated genes were identified. Four out of 11 downregulated genes (connective tissue growth factor, thrombospondin-1, collagen type I a1 and collagen type I a2) are known to be linked to inflammation and fibrosis. Results were verified across species in mesangial cells treated with a series of NO donors using Northern blot analysis, quantitative real-time PCR and protein analysis methods. Induction of endogenous NO production by cytokine stimulation also triggered regulation of the genes. One example gene, connective tissue growth factor, was studied at the promoter level. Promoter-reporter gene studies in mesangial cells demonstrated that NO acts at the transcriptional level to suppress gene expression. Our results reveal a complex role of NO in regulating gene expression in mesangial cells and suggest an antifibrotic potential for NO.

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Section: Discussionsupporting

confidence: 83%

Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

Wani

Carl²,

Henger³

et al. 2007

BCHM

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“…CTGF is a cytokine that acts downstream of TGF-␤1 to regulate matrix metabolism (30) and can induce fibroblast proliferation and matrix protein synthesis in vitro (31)(32)(33). In vivo, CTGF mRNA was reported to be elevated in experimental diabetic glomerulosclerosis (32), and serum CTGF levels were also increased in patients with systemic sclerosis (34) and other human renal diseases characterized by matrix deposition (35).…”

Section: Discussionmentioning

confidence: 99%

Excessive Matrix Accumulation in the Kidneys of MRL/lpr Lupus Mice Is Dependent on Complement Activation

Bao¹,

Zhou²,

Holers³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. Complement inhibition with Crry as the recombinant protein Crry-Ig has been demonstrated to prevent MRL/MpJ-Tnfrsf6 lpr (MRL/lpr) mice from developing proteinuria and renal failure. Crry-Ig-treated mice also showed less glomerulosclerosis compared with control MRL/lpr mice. To clarify how complement inhibition with Crry might affect renal scarring in lupus nephritis, gene transcript profiling was performed comparing Crry-Ig-treated MRL/lpr mice to controltreated MRL/lpr mice as well as to the MRL/ϩ strain control. Altered gene expression was confirmed by quantitative PCR, and protein quantity with either immunoblotting or immunofluorescence microscopy. Collagens I, III, IV, and VI were overexpressed in control MRL/lpr mice, whereas complement inhibition with Crry reduced the overexpression of these extracellular matrix components toward normal. Plasminogen activator inhibitor 1, connective tissue growth factor, and TGF-␤1 were upregulated in MRL/lpr mice compared with MRL/ϩ mice and were normalized by Crry-Ig treatment, suggesting that the product of these genes may contribute to the progressive glomerulosclerosis in MRL/lpr mice in a complement-dependent fashion. Thus, complement inhibition with Crry has a prominent effect on matrix-related genes and proteins, which translates into improvement in functional renal disease.The MRL/MpJ-Tnfrsf6 lpr (MRL/lpr) strain is a murine model of human systemic lupus erythematosus. These mice develop many features of human systemic lupus erythematosus, including autoantibodies, hypocomplementemia, and proliferative glomerulonephritis (GN) (1,2). MRL/lpr mice differ from the lupus-prone congenic MRL/ϩ strain by the nearly complete absence of the apoptosis-promoting membrane Fas protein, which is due to a retroviral insertion in the Tnfrsf6 (Fas) gene (3,4). In contrast to MRL/lpr mice, MRL/ϩ mice develop lupus very late in life, including only mild renal disease. Renal disease in MRL/lpr mice has similar features to the human disease it models, with mesangial proliferative GN early in disease and diffuse proliferative and crescentic GN later in the course. Ultimately, glomerulosclerosis and renal failure occur in the terminal phase of disease and are believed to cause death in these mice (5). Decreased serum C3 levels and deposition of C3 activation fragments and other complement components in kidney suggest that complement is involved in the pathogenesis of murine as well as human lupus nephritis (2).Complement activation can proceed via the classical, alternative, or mannose-binding lectin pathways (6). Activation through each of the three pathways leads to cleavage of C3 with generation of the proinflammatory and regulatory fragments C3a and C3b. C3b attaches covalently to immune complexes, which is followed by C5 binding and its cleavage to C5a and C5b. The former is a potent in...

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“…Patients with diabetes have increased TSP-1 in their plasma and kidneys (20). The expression of TSP-1 in mesangial cells was increased by high levels of glucose (21). TSP-1 promotes the events associated with diabetic nephropathy: mesangial cell proliferation and increased matrix production by mesangial cells (21)(22)(23)(24).…”

mentioning

confidence: 99%

“…The expression of TSP-1 in mesangial cells was increased by high levels of glucose (21). TSP-1 promotes the events associated with diabetic nephropathy: mesangial cell proliferation and increased matrix production by mesangial cells (21)(22)(23)(24). A peptide blocking the activation of transforming growth factor-␤ activation by TSP-1 prevented progression of cardiac fibrosis and improved cardiac function in a rat model, implicating TSP-1 in development of diabetic cardiomyopathy (25).…”

mentioning

confidence: 99%

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

Bhattacharyya

Marinic

Krukovets

et al. 2008

Journal of Biological Chemistry

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Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues (e.g. retinal neovascularization) and decreased in others (e.g. in skin). Molecular cell-and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications (atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up-regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This downregulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up-regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific posttranscriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cellspecific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.Despite the significant advances in the therapeutic methods to control blood glucose and insulin levels in diabetic patients, the precise regulation of these levels remains a problem. Vascular diabetic complications remain most prevalent and dangerous and account for the greatest numbers of deaths and hospitalizations in diabetic patients. The molecular basis for the vascular complications of diabetes is not well understood. Recent reports indicate that both microvascular and macrovascular complications of diabetes correlate directly with glucose levels in both patients and animal models (1-5). Some of these reports revealed the pathogenic role of impaired glucose tolerance and post-prandial hyperglycemia even in the absence of diabetes, e.g. (6). In vascular cells, glucose regulates expression of many genes that have been linked to the development of atherosclerosis or abnormal angiogenesis (reviewed in Ref. 7). One of them is thrombospondin-1 (TSP-1), 3 a cell matrix protein implicated in both atherogenesis (8 -12) and angiogenesis (13)(14)(15)(16)(17)(18)(19). Several lines of evidence indicate that TSP-1 may represent a lin...

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Suppression Subtractive Hybridization Identifies High Glucose Levels as a Stimulus for Expression of Connective Tissue Growth Factor and Other Genes in Human Mesangial Cells

Cited by 371 publications

References 39 publications

Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

Excessive Matrix Accumulation in the Kidneys of MRL/lpr Lupus Mice Is Dependent on Complement Activation

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

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