Role of integrin-linked kinase in epithelial–mesenchymal transition in crescent formation of experimental glomerulonephritis

Shimizu, Masaru; Kondo, Shuji; Urushihara, Maki; Takamatsu, Masanori; Kanemoto, Katsuyoshi; Nagata, Michio; Kubo, Shoji

doi:10.1093/ndt/gfl243

Cited by 49 publications

(36 citation statements)

References 39 publications

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“…However, the detailed mechanism that ILK is involved in TIF is still not well understood. Shimizu et al [28] suggested that the role of ILK in TIF might associate with EMT. They found that enhanced expression and activity of ILK was associated with the induction of EMT.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Integrin-Linked Kinase via a siRNA Expression Plasmid Attenuates Connective Tissue Growth Factor-Induced Human Proximal Tubular Epithelial Cells to Mesenchymal Transition

Liu

Li²,

Zhang³

et al. 2007

Am J Nephrol

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Background: Increasing evidence suggests that connective tissue growth factor (CTGF) is involved in the epithelial-to-mesenchymal transition (EMT). The exact intracellular events that drive this process, however, are not fully understood. In this study, we investigated the role of integrin-linked kinase (ILK) in mediating CTGF-induced EMT. Methods: The expression of α-smooth muscle actin (α-SMA) and E-cadherin upon the stimulation by recombinant human CTGF (rhCTGF) in cultured human tubular epithelial cell line (HK-2) was detected by real-time RT-PCR and Western blot. Subsequently, the role of ILK was determined by using ILK siRNA. Results: rhCTGF increased the mRNA expression of α-SMA significantly in a dose- and time-dependent manner, while E-cadherin mRNA decreased in a dose- and time-dependent manner. α-SMA protein was up-regulated after stimulation by 5 ng/ml CTGF for 96 h, and increased further after stimulation by 50 ng/ml. An immunocytochemical study showed that α-SMA was initially detectable at 48 h, and increased further at 72 h, while there was almost no α-SMA immunostaining observed in the control group at the same time point. E-cadherin protein was also down-regulated in a dose-dependent manner. Transfection of HK-2 cells with ILK-siRNA significantly attenuated rhCTGF-induced α-SMA induction and E-cadherin repression. Conclusion: Our study suggested that ILK mediated the effect of EMT in proximal tubular epithelial cells stimulated by CTGF.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Integrin-Linked Kinase via a siRNA Expression Plasmid Attenuates Connective Tissue Growth Factor-Induced Human Proximal Tubular Epithelial Cells to Mesenchymal Transition

Liu

Li²,

Zhang³

et al. 2007

Am J Nephrol

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“…TGF-␤ 1 is also strongly expressed in the cellular crescents [19] ( table 1 ). In human IgAN, where mesangial cell is the target of injury, mesangial immunostaining for active TGF-␤ 1 is almost negligible, despite increased mesangial TGF-␤ 1 mRNA levels.…”

Section: Tgf-␤ Expression In Hyperplastic Podocytes In the Diseased Gmentioning

confidence: 98%

“…In the TGF-␤ 1 transgenic mice, an acute and massive increase in plasma levels of TGF-␤ 1 results in severe GN with occasional crescent formation [17,18] . Indeed, TGF-␤ 1 is strongly expressed in the cellular crescents in the early stage of experimental crescentic GN [19] . Furthermore, podocytes covering the cellular lesion of FSGS exhibit increased expression of TGF-␤ 1 protein in human glomerular diseases [20,21] , and in Denys-Drash syndrome (DDS) mice [15] .…”

Section: Introductionmentioning

confidence: 98%

Effects of TGF-β on Podocyte Growth and Disease Progression in Proliferative Podocytopathies

Lee

Song²

2010

Kidney Blood Press Res

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Injured podocytes proliferate in cellular focal segmental glomerulosclerosis (FSGS), collapsing FSGS and crescentic glomerulonephritis, where TGF-β₁ is overexpressed in hyperplastic podocytes. Yet effects of podocyte TGF-β on podocyte growth and development of glomerulosclerosis have not been clearly defined. TGF-β activates Smads, Ras/extracellular signal-regulated kinase (ERK) and phosphatidyl inositol-3-kinase (PI3K) pathways in podocytes, of which the major TGF-β/Smad signaling pathway appears to override the minor TGF-β-induced Ras/ERK/PI3K pathways. We provide evidence that increasedTGF-β/Smad signaling activity by hyperplastic podocytes may lead to mesangial cell matrix overproduction and eventually to podocyte apoptosis and/or detachment, culminating in the development of glomerulosclerosis. In this regard, TGF-β, which is overexpressed by hyperplastic podocytes, may play an important role for the cellular and collapsing variants of FSGS to evolve into the classic FSGS pattern. In contrast, podocyte proliferation that is induced by Ras/ERK signaling activity in proliferative podocyte diseases seems to be mostly independent of TGF-β₁ activity. Collectively, these data bring new insights into our understanding of the overexpression of TGF-β in hyperplastic podocytes in progressive glomerular diseases.

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“…Growing evidence suggests that ILK is a critical mediator for tubular EMT induced by TGF-β 1 and CTGF [26,27,28], and likely plays a crucial role in podocyte damage, proteinuria and the pathogenesis of chronic renal fibrosis [29,30,31]. Forced expression of ILK in proximal tubular epithelial cells suppressed E-cadherin expression and induced fibronectin expression and its extracellular assembly [26].…”

Section: Introductionmentioning

confidence: 99%

Lipoxin A4 Inhibits Transition of Epithelial to Mesenchymal Cells in Proximal Tubules

Zhang

Tao

et al. 2010

Am J Nephrol

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Background: Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A₄ (LXA₄). It is speculated that LXA₄ could modulate the CTGF-induced epithelial to mesenchymal transition. Methods: The expressions of α-smooth muscle actin (α-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of α-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2). Results: Pretreatment of HK-2 cells with LXA₄ inhibited the morphological fibroblast-like changes and α-SMA expression induced by CTGF but not by transforming growth factor-β₁ (TGF-β₁). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-β₁ were increased by LXA₄. LXA₄ inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA₄ did not affect TGF-β₁-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2’s binding to Smad-4 and subsequent nuclear translocation. Conclusion: LXA₄ inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-β₁, via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.

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Role of integrin-linked kinase in epithelial–mesenchymal transition in crescent formation of experimental glomerulonephritis

Cited by 49 publications

References 39 publications

Inhibition of Integrin-Linked Kinase via a siRNA Expression Plasmid Attenuates Connective Tissue Growth Factor-Induced Human Proximal Tubular Epithelial Cells to Mesenchymal Transition

Inhibition of Integrin-Linked Kinase via a siRNA Expression Plasmid Attenuates Connective Tissue Growth Factor-Induced Human Proximal Tubular Epithelial Cells to Mesenchymal Transition

Effects of TGF-β on Podocyte Growth and Disease Progression in Proliferative Podocytopathies

Lipoxin A4 Inhibits Transition of Epithelial to Mesenchymal Cells in Proximal Tubules

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