ERK5 Regulates Glucose-Induced Increased Fibronectin Production in the Endothelial Cells and in the Retina in Diabetes

Wu, Yuexiu; Feng, Biao; Chen, Shali; Chakrabarti, Subrata

doi:10.1167/iovs.12-10553

Cited by 15 publications

(4 citation statements)

References 48 publications

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“…ECs, being the first cell type exposed to high blood glucose levels, play a major role in the pathogenesis of chronic diabetic complications [3,29,52]. We carried out in vivo experiments in the retinal capillary ECs.…”

Section: Discussionmentioning

confidence: 99%

miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes

Chen¹,

Feng²,

Thomas³

et al. 2017

PLoS ONE

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Hyperglycemic damage to the endothelial cells (ECs) leads to increased synthesis of inflammatory cytokines. We have previously shown miR-146a downregulation in ECs and in the tissues of diabetic mice. Here we investigated the role of miR-146a, in the production of specific inflammatory cytokines and extracellular matrix (ECM) proteins in retina and kidneys in diabetes. We generated an endothelial specific miR-146a overexpressing transgenic mice (TG). We investigated these mice and wild type (WT) controls with or without streptozotocin (STZ) induced diabetes. Retinal and renal cortical tissues from the mice were examined for mRNAs for specific inflammatory markers, (ECM) proteins and inflammation inducible transcription factor by real time RT-PCR. Corresponding proteins, where possible, were examined using immunofluorescence or ELISA. In parallel, we examined ECs following incubation with various levels of glucose with or without miR-146a mimic transfection. In the retina and kidneys of WT mice with diabetes, increased expression of inflammatory markers (IL-6, TNFα, IL1β) in association augmented expression of ECM proteins (collagen 1αIV, fibronectin) and NF κB-P65 were observed, compared to WT non-diabetic controls. These changes were prevented in diabetic miR-146a TG mice along with retinal and renal functional and structural changes. In vitro studies showed similar changes in the ECs exposed to high glucose. Such changes were corrected in the cells following miR-146a mimic transfection. Further analyses of renal cortical tissues showed diabetes induced significant upregulation of two regulators of NFκB, namely Interleukin-1 associated Kinase 1 and tumour necrosis factor receptor associated factor. Such changes were prevented in diabetic TG animals. These data indicate that augmented production of inflammatory cytokines and ECM proteins in the retina and kidneys in diabetes are regulated through endothelium derived miR-146a. Identification of such novel mechanisms may potentially lead to the development of novel therapies.

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Section: Discussionmentioning

confidence: 99%

miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes

Chen¹,

Feng²,

Thomas³

et al. 2017

PLoS ONE

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“…They have found that ERK5 inactivation results in augmented VEGF mRNA expression which contributes to DR-associated neovascularization in rats [ 13 ]. Moreover, they have shown that ERK5 signaling may play a role in the glucose-induced increases in fibronectin production in DR [ 14 ]. Together, these studies and our work highlight a potential role of ERK5 signaling in the pathogenesis of DR. Future studies may examine the ERK5 and its activated form in patients’ specimens to figure out whether ERK5 signaling is similarly important in DR development in humans, like in rodents.…”

Section: Discussionmentioning

confidence: 99%

Molecular regulation of ERK5 in development of diabetic retinopathy

et al. 2017

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Diabetic retinopathy (DR) is a major complication of diabetes, and causes pathological changes in retina blood vessels, as the most common cause of vision loss. Extracellular-signal-regulated kinase 5 (ERK5) is the newest discovered member in the mitogen-activated protein kinases (MAPKs) family, and recent evidence demonstrates an essential role of ERK5 signaling in the angiogenesis. However, whether ERK5 signaling may regulate DR development is unknown. Here, we used a streptozocin (STZ)-induce mouse DR model to investigate this question. We detected significant increases in the phosphorylation of ERK5, a signature of ERK5 activation in the purified retinal endothelial cells in DR mice, compared to control mice. In vivo suppression of ERK5 phosphorylation through administration of a specific inhibitor of ERK5 activation, BIX02189, did not prevent the occurrence of STZ-induced diabetes in mice, but significantly alleviated the severity of DR, seemingly through attenuating the retina neovascularization. Thus, our study suggests a previously unappreciated role of ERK5 signaling in DR development.

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“…In pulmonary fibrosis Erk5 also appears to be necessary for the production of ECM by fibroblasts and epithelial cells, however, in this case it is associated with Smad3 acetylation; acetylation of Lys19 on Smad3 enhances the binding of Smad3 to DNA (Kim et al, 2013). The activation of Erk5 by glucose in retinal and vascular endothelial cells causes a significant rise in fibronectin expression, a feature of diabetic retinopathy (Wu et al, 2012). Interestingly, in these experiments the effect of Erk5 may be Smad-independent as expression of constitutively active Erk5 was associated with a decrease in Smad2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Erk5 is a mediator to TGFÎ²1-induced loss of phenotype and function in human podocytes

2014

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Background: Podocytes are highly specialized cells integral to the normal functioning kidney, however, in diabetic nephropathy injury occurs leading to a compromised phenotype and podocyte dysfunction which critically produces podocyte loss with subsequent renal impairment. TGFβ1 holds a major role in the development of diabetic nephropathy. Erk5 is an atypical mitogen-activated protein (MAP) kinase involved in pathways modulating cell survival, proliferation, differentiation, and motility. Accordingly, the role of Erk5 in mediating TGFβ1-induced podocyte damage was investigated.Methods: Conditionally immortalized human podocytes were stimulated with TGFβ1 (2.5 ng/ml); inhibition of Erk5 activation was conducted with the chemical inhibitor BIX02188 (10 μM) directed to the upstream Mek5; inhibition of Alk5 was performed with SB431542 (10 μM); Ras signaling was inhibited with farnesylthiosalicylic acid (10 μM). Intracellular signaling proteins were investigated by western blotting; phenotype was explored by immunofluorescence; proliferation was assessed with a MTS assay; motility was examined with a scratch assay; barrier function was studied using electric cell-substrate impedance sensing; apoptosis was studied with annexin V-FITC flow cytometry.Results: Podocytes expressed Erk5 which was phosphorylated by TGFβ1 via Mek5, whilst not involving Ras. TGFβ1 altered podocyte phenotype by decreasing P-cadherin staining and increasing α-SMA, as well as reducing podocyte barrier function; both were prevented by inhibiting Erk5 phosphorylation with BIX02188. TGFβ1-induced podocyte proliferation was prevented by BIX02188, whereas the induced apoptosis was not. Podocyte motility was reduced by BIX02188 alone and further diminished with TGFβ1 co-incubation.Conclusion: These results describe for the first time the expression of Erk5 in podocytes and identify it as a potential target for the treatment of diabetic renal disease.

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ERK5 Regulates Glucose-Induced Increased Fibronectin Production in the Endothelial Cells and in the Retina in Diabetes

Cited by 15 publications

References 48 publications

miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes

miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes

Molecular regulation of ERK5 in development of diabetic retinopathy

Erk5 is a mediator to TGFÎ²1-induced loss of phenotype and function in human podocytes

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