Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Qiu, Lianqun; Sinniah, Raja; Hsu, Shu-Hui

doi:10.1038/labinvest.3700144

Cited by 24 publications

(30 citation statements)

References 43 publications

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“…This observation is in contrast to the findings of Shankland et al [28], who noted decreased p27 expression during the mesangioproliferative phase of anti-thymocyte plasma-induced glomerulonephritis in rats. Additionally, in renal biopsy specimens of patients with IgA nephropathy, a decrease of glomerular p27 expression was found in proliferative and sclerosing lesions [29]. Upregulation of glomerular p27 expression leads to cell hypertrophy [30], whereas proliferation is associated with a decrease in p27 levels [31].…”

Section: Discussionmentioning

confidence: 99%

Y-Box Protein 1 Stimulates Mesangial Cell Proliferation via Activation of ERK1/2

Feng

Huang

Zhang

et al. 2009

Nephron Exp Nephrol

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Aims: To investigate the effects of Y-box protein 1 (YB-1) on the mitogen-activated protein kinase pathway to ascertain which signaling pathway is involved in YB-1-induced mesangial cell (MC) proliferation. Methods: The rat MC line HBZY-1 was transfected with pcDNA3.1-YB-1. Cell proliferation was determined by [³H]thymidine incorporation, cell counting and cell-cycle analysis. The expression of cyclins was examined by real-time RT-PCR and immunoblotting analysis. Phosphorylation of c-Raf, MEK1/2, and ERK1/2 was detected by immunoblotting analysis. Results: MCs transfected with YB-1 showed an increased DNA synthesis and number of cells in the S and G2 phases of the cell cycle. The expression of cyclins (cyclin A2, cyclin D1, cyclin E and p27) was increased, while p21 levels were decreased. The expression levels of phosphorylated c-Raf kinase, MEK1/2 and the ERK1/2 proteins were elevated in MCs transfected with YB-1. YB-1-stimulated cell proliferation was blocked by U0126, a specific inhibitor of ERK1/2. ERK1/2 regulated YB-1 expression in MCs stimulated with TGF-β, an effect that was inhibited by U0126. Conclusions: YB-1 has an apparent stimulatory effect on c-Raf, MEK1/2, ERK1/2 and cell-cycle progression in MCs, after which activated ERK1/2 goes on to upregulate YB-1 expression and augment the proliferative effect of YB-1.

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Section: Discussionmentioning

confidence: 99%

Y-Box Protein 1 Stimulates Mesangial Cell Proliferation via Activation of ERK1/2

Feng

Huang

Zhang

et al. 2009

Nephron Exp Nephrol

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“…In cases of disagreement in the scoring, the process was repeated and the final score was For semi-quantitative analysis, glomerular endothelial and mesangial cells were counted together. In addition, a seven-point scoring system was employed for the evaluation of podocyte positive signals (NF-κB, p65, p50, TNF-α and IL-1β) in glomeruli that took both intensity and extent into account [34,36]. Podocytes were primarily identified by architectural features revealed on light microscopy by mild PAS counterstaining.…”

Section: Semi-quantitative Histological Analysismentioning

confidence: 99%

In situ glomerular expression of activated NF-κB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy

2005

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Nuclear Factor-kappaB (NF-kappaB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular injury. We investigated the potential role of NF-kappaB activation in the pathogenesis of glomerular injury in 31 patients with class III-V lupus nephritis (LN), 14 patients with non-proliferative proteinuric glomerulopathy and six normal controls. The expression of NF-kappaB subunits p65 and p50, and the NF-kappaB regulated proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) as well as CD68 and synaptopodin was examined by Southwestern histochemistry (SWH) or immunohistochemistry. In contrast to non-proliferative glomerulopathy and normal controls, NF-kappaB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating cells in class IV LN, along with upregulation of TNF-alpha, IL-1beta, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial activation of NF-kappaB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage infiltration. Podocyte NF-kappaB overactivation (predominantly p65) paralleled podocyte expression of TNF-alpha and IL-1beta in patients with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-kappaB and p65 were positively correlated with the severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-kappaB in glomerular injury by multiple mechanisms.

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“…KLF15 binds to the GC-rich region of the promoter for transcription factor E2F1 [11], which regulate the expression of cell cycle proteins [31]. The initiation and amplification of mesangial cell proliferation have been linked to glomerular sclerosis and the downregulation of mesangial cell E2F1 expression in human IgA nephropathy [32]. In this study, siRNA target to E2F1 was cotransfected with siKLF15 into RMCs; the results indicated that increase of cell proliferation induced by siKLF15 can be eliminated partly by siE2F1.…”

Section: Discussionmentioning

confidence: 97%

Kruppel-like Factor-15 Inhibits the Proliferation of Mesangial Cells

Hong

Cui²,

Xie³

et al. 2012

Cell Physiol Biochem

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Background/Aims: The Kruppel-like factor-15 (KLF15), a DNA-binding transcription factor, is highly expressed in endothelial and mesangial cells of the kidney. However, its effects on mesangial cell proliferation have not previously been investigated. In this study, we investigated the effect of KLF15 on mesangial cell proliferation. Methods: We established a classic rat anti-Thy1 mesangial proliferative nephritis model. Affymetrix rat U230 2.0 chip was used to detect the gene expression profiles at different time point in the model. The different expression of KLF15 was shown during mesangial cell proliferation period and proliferation declined period of anti-Thy1 nephritis model by microarray analysis, Real-time PCR and Western blotting. Then we determined the effects of KLF15 and its downstream target, cell cycle regulation factor E2F1 on the proliferation of mesangial cells and the expression of the positive-acting cell cycle regulatory proteins, cyclinD1 and CDK2, by means of positive and negative interference experiments in cultured rat mesangial cells. We detected also protein expression of E2F1, cyclinD1 and CDK2 in vivo. Results: By real-time PCR, Western blotting, and microarray analysis, KLF15 expression was shown to be lower during mesangial cell proliferation period and higher during proliferation declined period and under normal conditions. The mesangial cell proliferation was reduced and the expression of E2F1, cyclin D1 and CDK2 was downregulated in mesangial cells overexpressing KLF15. When KLF15 expression was inhibited by siRNA, the expression of E2F1, cyclin D1 and CDK2 and mesangial cell proliferation were increased. When E2F1 was inhibited by siRNA, protein level of CDK2 and cyclin D1 were lower than control. When siE2F1 was co-transfected with siKLF15 into mesangial cells, the increase of cell proliferation induced by siKLF15 was eliminated partly by siE2F1. Moreover, E2F1, cyclin D1 and CDK2 were higher expression during mesangial cell proliferation period, and were downregulated during proliferation declined period in vivo. Conclusions: These results suggest that KLF15 inhibits mesangial cell proliferation, possibly by regulating the expression of cell cycle regulation proteins through E2F1. Thus, KLF15 may be a useful target for therapeutic intervention in mesangial proliferative glomerulonephritis.

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Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Cited by 24 publications

References 43 publications

Y-Box Protein 1 Stimulates Mesangial Cell Proliferation via Activation of ERK1/2

Y-Box Protein 1 Stimulates Mesangial Cell Proliferation via Activation of ERK1/2

In situ glomerular expression of activated NF-κB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy

Kruppel-like Factor-15 Inhibits the Proliferation of Mesangial Cells

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