EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

Chen, Shiguo; Chen, Jian Kang; Nagai, Kojiro; Plieth, David; Tan, Mingqi; Lee, Tang Cheng; Threadgill, David W.; Neilson, Eric G.; Harris, Raymond C.

doi:10.1681/asn.2011070645

Cited by 239 publications

(266 citation statements)

References 38 publications

(47 reference statements)

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“…Boosting survival and regeneration of TECs might be renoprotective and antifibrotic as, for example, suggested for CSF-1 (143). Other TECs factors driving fibrosis include Notch (144), lipocalin-2 (NGAL) (28), kidney injury molecule-1 (KIM-1) (145), b-catenin signaling (146), and the EGFR (147,148). Paracrine signaling from damaged TECs is probably one of a major mechanisms driving renal fibrosis ( Figure 3).…”

Section: The Role Of Glomerular Cellsmentioning

confidence: 98%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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Section: The Role Of Glomerular Cellsmentioning

confidence: 98%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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“…1 Our recent studies demonstrated that NADPH oxidase-derived ROS production-mediated c-Src kinase activation was an upstream mediator of EGFR activation in renal proximal tubular epithelial cells in response to chronic angiotensin II treatment. 15 A recent study also indicated that inhibition of c-Src kinase prevented progression of diabetic nephropathy. 27 To examine whether NADPH oxidase-dependent ROS production induced c-Src kinase-dependent activation of the EGFR-ERK signaling pathway and TGF-b-Smad2/3 signaling pathway in podocytes, WT diabetic mice were administered a mitochondria-targeted ROS scavenger, mito-tempol (10 mg/kg per day intraperitoneally), or a cell-permeable NADPHoxidase inhibitor, apocynin (5mg/kg per day intraperitoneally), for 3 weeks with the first dose being given 2 days after initiation of diabetes.…”

Section: Ros-mediated Podocyte C-src and Egfr/erk Phosphorylationmentioning

confidence: 99%

“…26 Our previous study found that in response to chronic angiotensin II infusion in renal proximal tubule epithelial cells, TGF-b-Smad2/3 signaling pathway was activated through a c-Src kinasemediated EGFR-ERK signaling pathway activation. 15 To determine whether the TGF-b signaling pathway was activated in diabetic podocytes through an EGFR-dependent mechanism, we examined and found increased phosphorylation levels of EGFR at three different sites (Y845, Y1068 and Y1173) as well as increased phosphorylation of c-Src, ERK1/2 as well as Smad2/3. The expression levels of TGF-b and fibronectin were upregulated in the glomeruli isolated from WT diabetic mice.…”

Section: Podocyte Egfr Deletion Attenuated Albuminuria and Podocyte Lossmentioning

confidence: 99%

“…11,12 Aberrant EGF receptor signaling pathway activations is associated with tumorogenesis, 12,13 and we and other investigators have demonstrated that the EGFR activation is a pivotal mediator for renal fibrosis and may interact with TGF-b signaling. [14][15][16][17] In this study, we investigated the role of podocyte EGFR in the development of diabetic nephropathy by using podocyte-specific EGFR deletion mice and determined that hyperglycemia-induced ROS production activates the Src kinase and thereby induces EGFR activation-dependent phosphorylation of ERK, activation of the TGF-b-Smad2/3 signaling pathway, downregulation of Bcl2, and upregulation of cleaved caspase 3 and leads to a reduction of the podocyte number per glomerulus and development of albuminuria, the hallmarks of early diabetic nephropathy.…”

mentioning

confidence: 99%

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EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Chen¹,

Chen

Harris

2015

Journal of the American Society of Nephrology

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113

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The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR podKO ) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR podKO mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR podKO diabetic mice had less TGF-b1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR podKO diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-b1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-b1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.

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“…2). These sites are directly involved in activating the RAS, MAPK, PI3K, and c-Src pathways (27,47,48) and indirectly lead to activation of WNT, NF-B, and TGF-␤ signaling via these former pathways. Hence, these particular phosphorylation sites were examined as they activate pathways previously found to be inhibited by NDRG1 in these cells (4,6,8,(17)(18)(19).…”

Section: Panel II and C Panel Ii)mentioning

confidence: 99%

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

Kovačević

Menezes

Sahni

et al. 2016

Journal of Biological Chemistry

113

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N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-␤ pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

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EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

Cited by 239 publications

References 38 publications

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Renal Allograft Fibrosis: Biology and Therapeutic Targets

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

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