Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

Xin, Xiping; Khan, Zia A.; Chen, Shali; Chakrabarti, Subrata

doi:10.1038/labinvest.3700178

Cited by 55 publications

(71 citation statements)

References 33 publications

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“…We have also demonstrated that ET-induced fibronectin mRNA production may also be mediated via MAPK signalling [10]. Moreover, the current study and other investigations in the literature indicate that MAPK may influence PKB activation [19,33].…”

Section: Discussionmentioning

confidence: 66%

“…Such molecular changes may arbitrate glucose-induced signals for fibronectin mRNA expression. We have previously demonstrated that mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) may cause fibronectin mRNA and protein upregulation [10]. It is increasingly being realised that such protein kinase pathways may also interact and cross-talk with cellular process regulation [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

et al. 2005

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Aims/hypothesis: Increased expression and decreased degradation of extracellular matrix (ECM) proteins are key features of chronic diabetic complications. Fibronectin, a predominant ECM protein, has been shown to be overexpressed in all target organs of diabetic complications and in endothelial cells cultured in high levels of glucose. The present study was designed to elucidate the role of protein kinase B (Akt/PKB) in glucose-induced fibronectin mRNA expression and protein production in vascular endothelial cells. Methods: Human umbilical vein endothelial cells were cultured in the presence of high glucose to study Akt/PKB activation. The upstream and downstream mediators in the Akt/PKB pathway were also investigated using dominant negative transfections and specific inhibitors of signalling pathways. Cells were subjected to real time RT-PCR, western blotting, and confocal microscopy to assess Akt1/PKBα activation and fibronectin mRNA expression and protein production. To detect transcription factor activation, electrophoretic mobility shift assay was carried out. Results: Our data demonstrate that fibronectin mRNA expression and protein production that are induced by high glucose are mediated via activation of Akt/PKB, which is modulated by mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase C. Glucose-induced fibronectin mRNA expression and protein production are also mediated by Akt1/PKBα-dependent activation of the transcription factors nuclear factor-κB and activating protein-1. Conclusions/interpretation: Our study provides insight into the mechanical basis of glucoseinduced increases in fibronectin mRNA expression and protein production. High levels of glucose may increase fibronectin mRNA expression and protein production by activating Akt/PKB.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

et al. 2005

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“…Our results indicate that high glucose levels lead to increased transcriptional upregulation of p300. The signaling mechanisms of this glucose-induced effect were examined following treatment of the endothelial cells to pharmacological inhibitors of signaling pathways known to be altered in diabetes (21,22,24). The results showed that p300 mRNA expression was downregulated by inhibitors of the MAPK, PKC, and PKB pathway (Fig.…”

Section: P300 In Ecm Expressionmentioning

confidence: 99%

“…RNA isolation and cDNA synthesis. Trizol reagent (Invitrogen, Burlington, ON, Canada) was used to isolate total RNA as described (21,22). First-strand cDNA synthesis was performed using Superscript-II system (Invitrogen).…”

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confidence: 99%

Diabetes-Induced Extracellular Matrix Protein Expression Is Mediated by Transcription Coactivator p300

et al. 2006

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Increased fibronectin expression is a key feature of diabetic angiopathy. We have previously shown that nuclear factor-B (NF-B) mediates fibronectin expression in endothelial cells and in organs affected by diabetes complications. p300, a transcription coactivator, may regulate NF-B activity via poly(ADP-ribose) polymerase (PARP) activation. Hence, we examined the role of p300 in fibronectin expression in diabetes. High glucose induced fibronectin expression in the endothelial cells, which was associated with increased p300, PARP activity, and NF-B activation. This p300 alteration is mediated by mitogenactivated protein kinase and protein kinase C and B. We then used p300 small interfering RNA (siRNA) and showed decreased fibronectin and PARP expression, as well as NF-B activation, in the endothelial cells. Examination of the heart tissues of streptozotocin-induced diabetic mice revealed increased fibronectin and p300 mRNA. Intravenous injection of p300 siRNA resulted in decreased p300 levels and normalized fibronectin expression in the heart. We further investigated retinal tissues from streptozotocin-induced diabetic rats treated with intravitreal p300 siRNA injection. Similar to the heart, p300 siRNA inhibited fibronectin expression in the retina of the diabetic animals. These results indicate that transcriptional coactivator p300 may regulate fibronectin expression via PARP and NF-B activation in diabetes. Diabetes 55:3104 -3111, 2006

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“…Fibronectin expression was shown to increase in an ERK/MAPK dependent manner in endothelial cells following stimulation with high levels of glucose [31].…”

Section: Discussionmentioning

confidence: 99%

Intracellular signaling via ERK/MAPK completes the pathway for tubulogenic fibronectin in MDCK cells

Zhao

Greco

Hellman

et al. 2007

Biochemical and Biophysical Research Communications

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A classic in vitro model of branching morphogenesis utilizes the Madin-Darby canine kidney (MDCK) cell line. MDCK Strain II cells form hollow monoclonal cysts in a three-dimensional collagen matrix over the course of ten days and tubulate in response to hepatocyte growth factor (HGF). We and our colleagues previously showed that activation of the extracellular-signal regulated kinase (ERK, aka MAPK) pathway is necessary and sufficient to induce tubulogenesis in MDCK cells. We also showed in a microarray study that one of the genes upregulated by HGF was the known tubulogene fibronectin. Given that HGF activates a multitude of signaling pathways, including ERK/ MAPK, to test the intracellular regulatory pathway, we used two distinct inhibitors of ERK activation (U0126 and PD098059). Following induction of MDCK Type II cells with HGF, tubulogenic fibronectin mRNA was upregulated 4-fold by real time PCR, and minimal or no change in fibronectin expression was seen when HGF was added with either U0126 or PD098059. We confirmed these results using an MDCK cell line inducible for Raf, which is upstream of ERK. Following activation of Raf, fibronectin mRNA and protein expression were increased to a similar degree as was seen following HGF induction. Furthermore, MDCK Strain I cells, which originate from collecting ducts and have constitutively active ERK, spontaneously initiate tubulogenesis. We show here that MDCK Strain I cells have high levels of fibronectin mRNA and protein compared to MDCK Strain II cells. When U0126 and PD098059 were added to MDCK Strain I cells, fibronectin mRNA and protein levels were decreased to levels seen in MDCK Strain II cells. These data allow us to complete what we believe is the first description of a tubulogenic pathway from receptor/ligand (HGF/CMET), through an intracellular signaling pathway (ERK/MAPK), to transcription and, finally, secretion of a critical tubuloprotein (fibronectin).

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Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

Cited by 55 publications

References 33 publications

Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells

Diabetes-Induced Extracellular Matrix Protein Expression Is Mediated by Transcription Coactivator p300

Intracellular signaling via ERK/MAPK completes the pathway for tubulogenic fibronectin in MDCK cells

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