Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo

Fragiadaki, Maria; Witherden, Abigail S.; Kaneko, Toshinobu; Sonnylal, Sonali; Pusey, Charles D.; Bou‐Gharios, George; Mason, Roger M.

doi:10.1016/j.matbio.2011.07.004

Cited by 41 publications

(33 citation statements)

References 32 publications

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“…However, conclusive evidence of a full EMT process in vivo is a controversial point. In fact, some papers provide evidence in vivo of human and rodent tubular cell EMT as a source of matrix-producing interstitial fibroblasts (Iwano et al, 2002;Rastaldi et al, 2002;Burns et al, 2006), and of mouse tubular cells producing collagen without evidence of EMT (Koesters et al, 2010;Fragiadaki et al, 2011). Instead, other in vivo models show that interstitial pericytes and resident fibroblasts, but not tubular cells, might be myofibroblast progenitors (Lin et al, 2008;Humphreys et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelialmesenchymal transition (EMT) affects tubular cells, which under highglucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used. These cells showed an elongated morphology, stress fibers and vimentin increment but maintained most of the epithelial marker expression and distribution. In these cells exposed to high glucose, which overexpressed and secreted active TGF-β1, Arg protein and activity was downregulated. A further TGF-β1 increase was induced by Arg silencing with siRNA, as with the Arg tyrosine kinase inhibitor Imatinib. In the cells exposed to high glucose, reactive oxygen species (ROS)-dependent Arg kinase downregulation induced both RhoA activation, through p190RhoGAPA (also known as ARHGAP35) modulation, and proteasome activity inhibition. These data evidence a new specific involvement of Arg kinase into the regulation of TGF-β1 expression in tubular cells under high-glucose conditions and provide cues for new translational approaches in diabetic nephropathy.

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Section: Introductionmentioning

confidence: 99%

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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“…The current study focuses primarily on the dermal and pulmonary compartment, the most profoundly affected tissues in the Col1a2-CTGF transgenic mice (Sonnylal et al, 2010). In most organs Col1a2 expression is located in cells of mesenchymal origin (Bou-Gharios et al, 1996), however in kidney, expression has also been observed in tubular epithelial cells upon injury (Fragiadaki et al, 2011). Interestingly, in a study using administration of aristolochic acid (AA) to induce renal fibrosis, the Col1a2-CTGF transgenic mice did not exhibit more fibrosis compared with wt AA-treated mice (Fragiadaki et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In most organs Col1a2 expression is located in cells of mesenchymal origin (Bou-Gharios et al, 1996), however in kidney, expression has also been observed in tubular epithelial cells upon injury (Fragiadaki et al, 2011). Interestingly, in a study using administration of aristolochic acid (AA) to induce renal fibrosis, the Col1a2-CTGF transgenic mice did not exhibit more fibrosis compared with wt AA-treated mice (Fragiadaki et al, 2011). This is however perhaps not surprising as AAadministration at the similar dose range (5-10 mg/kg) has been shown to induce as severe nephropathy resulting in florid interstitial inflammation with immune cell infiltrates and severe tissue damage and necrosis (Pozdzik et al, 2008;Zhou et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor causes EMT-like cell fate changes in vivo and in vitro

Sonnylal

Jones

et al. 2013

Journal of Cell Science

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SummaryConnective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for aSMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells coexpressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGFb, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of a-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.

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“…It is possible that TEC undergoing EMT-like changes may become local producers of ECM. 16 Migration across basement membrane as in EMT of cancer (type III) or embryonic cells (type I) may not be a feature of the EMT of epithelial cells (type II) in fibrotic diseases. 17 MMP-9 is well established to have a role in tubular cell EMT, 9,18 in fact induction of tubular cell EMT in vitro and in vivo is associated with increased expression of MMP-9.…”

mentioning

confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

129

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo

Cited by 41 publications

References 32 publications

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Connective Tissue Growth Factor causes EMT-like cell fate changes in vivo and in vitro

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

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