Functional consequences of integrin-linked kinase activation in podocyte damage

Teixeira, Vicente de Paulo Castro; Blattner, Simone M.; Li, Min; Anders, Hans‐Joachim; Cohen, Clemens D.; Edenhofer, Ilka; Calvaresi, Novella; Merkle, Monika; Rastaldi, Maria Pia; Kretzler, Matthias

doi:10.1111/j.1523-1755.2005.67108.x

Cited by 72 publications

(30 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, the established regulatory effect of increased ILK-1 expression on E-cadherin transcriptional expression (39) suggests an important role for this serine-threonine kinase in regulating E-cadherin expression in the early postinjury phase when whole-lung ILK-1 expression is increased. ILK-1-mediated E-cadherin repression and inhibition of GSK3␤ activity (40) has been implicated in EMT (41,42) and may explain in part the prominent epithelial and interstitial cellular proliferation to BHT/O 2 (15,16). Bailey and colleagues (43) have shown that peroxide-induced injury of cultured retinal pigment epithelial cells results in reduced junctional N-cadherin protein expression and ␤-catenin nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

Douglas

Valle

Winn

et al. 2006

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of noncanonical ␤-catenin pathway proteins E-cadherin, integrin-linked kinase-1, and ␤-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O 2 ) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, collagen deposition, interstitial cellular proliferation, and lung architectural distortion. Reduced E-cadherin expression after 6 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of ␤-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. ␤-Catenin expression was reduced in z-ASP-co-treated lungs after BHT/hyperoxia. The noncanonical cadherin-␤-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury. Keywords: ␤-catenin; E-cadherin; lung injury repair; cell junctions; caspase Resolution of alveolar epithelial/capillary membrane damage after acute lung injury (ALI) requires coordinated and effective tissue reconstruction to reestablish a functional barrier. In particular, restoration of the normal air space architecture requires reconstitution of denuded type I alveolar epithelial cells that undergo apoptotic and necrotic death during the exudative phase of ALI. Coordination of extracellular matrix turnover and regeneration of type II epithelial cells is important in reestablishing surfactant production and ion transport (1). Orderly re-epithelialization suppresses fibroblast proliferation and matrix deposition after ALI (1, 2). However, resolution of ALI can result in disordered repair of the alveolus, characterized by impaired fibrinolysis of the in-

show abstract

Section: Discussionmentioning

confidence: 99%

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

Douglas

Valle

Winn

et al. 2006

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…LXA 4 did not affect Smad signaling, ILK induction or EMT induced by TGF-β 1 . Proposed mechanisms based on our and previous observations [12,26,29,30,37,39,48,49,50] on the signaling pathway involved in CTGF- and TGF-β 1 -induced EMT and the role of LXA 4 are summarized and illustrated in figure 8. Our results further expand on the antifibrotic repertoire of lipoxins [18], which represent useful tools for the development of a new treatment for renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…It has been reported that CD2AP also is expressed in the podocyte and that CD2AP is involved in maintaining the barrier function of the slit diaphragm by interacting with nephrin (24 -29). It also has been reported that the expression of CD2AP is decreased in cultured podocyte that is treated with PAN (30,31). All of the properties of these synaptic vesicle-associated molecules prompted us to consider that SV2B might be associated with the slit diaphragm.…”

mentioning

confidence: 99%

Synaptic Vesicle Protein 2B Is Expressed in Podocyte, and Its Expression Is Altered in Proteinuric Glomeruli

Miyauchi

Saito²,

Karasawa³

et al. 2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Synaptic vesicle protein 2B (SV2B) was identified by the subtraction hybridization technique as a molecule of which mRNA expression was decreased in puromycin aminonucleoside (PAN) nephropathy by glomerular cDNA subtraction assay. The expression of SV2B was detected in glomerular lysate with Western blot analysis. Dual-labeling immunofluorescence studies with glomerular cell markers demonstrated that SV2B is expressed in glomerular visceral epithelial cells (podocytes). The expression of SV2B is detected also in cultured podocyte and in human kidney section as podocytic pattern. The decrease of SV2B mRNA was already detected before the onset of proteinuria in PAN nephropathy. The mRNA expression of SV2B clearly is altered not only in PAN nephropathy but also in another proteinuric state that is caused by an antibody against nephrin, a functional molecule of the slit diaphragm. The decreased intensity in SV2B staining was already detected before the peak of proteinuria in both models with immunofluorescence study. A reduced amount of SV2B was detected in both models also with Western blot analysis. CD2AP, another functional molecule of the slit diaphragm, was observed in cytoplasm, including the processes area of the cultured podocyte, and when the podocyte was treated with small interfering RNA for SV2B, CD2AP staining at the process area was not detected. These results suggest that SV2B is a functional molecule of podocyte, and SV2B may play a role in the expression and proper localization of CD2AP.

show abstract

Functional consequences of integrin-linked kinase activation in podocyte damage

Abstract: ILK regulates podocyte cell matrix interaction, proliferation, and slit membrane gene expression in podocyte damage. As this pathway is amendable to pharmacologic intervention, further detailed studies of in vivo ILK function in glomerular disease appear justified.

Cited by 72 publications

References 40 publications

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

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

Synaptic Vesicle Protein 2B Is Expressed in Podocyte, and Its Expression Is Altered in Proteinuric Glomeruli

Contact Info

Product

Resources

About