Please use this identifier to cite or link to this item:
http://dx.doi.org/10.25673/32049.2
Title: | Knock-out of vascular smooth muscle epidermal growth factor receptor prevents obesity-induced vascular dysfunction and renal damage in vivo |
Author(s): | Stern, Christian Schreier, Barbara Nolze, Alexander Rabe, Sindy Mildenberger, Sigrid Gekle, Michael |
Issue Date: | 2020-02-06 |
Type: | Dataset |
Language: | English |
Subjects: | Diabetes, Epidermal growth factor receptor, Aorta, Kidney, Next generation sequencing, Mouse, Serum response factor, Renal damage, Vascular dysfunction |
Abstract: | Aim: Obesity causes diabetes type 2 (DMT2) leading to vascular dysfunction and finally renal end-organ damage. Vascular smooth muscle (VSM) EGF receptor (EGFR) modulates vascular wall homeostasis in part via serum response factor (SRF), a major regulator of VSM differentiation and a sensor for glucose. We investigated the role of VSM-EGFR during obesityinduced renovascular dysfunction and the underlying mechanisms related to EGFRhyperglycemia crosstalk. Methods: The role of VSM-EGFR during high fat diet (HFD)-induced DMT2 was investigated in a mouse model with inducible, VSM-specific EGFR knock out (KO). Various structural and functional parameters as well as transcriptome changes in vivo and ex vivo were assessed. The impact of hyperglycemia on EGFR-induced signaling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results: We show that VSM-EGFR mediates obesity/DMT2-induced vascular dysfunction, remodeling and transcriptome dysregulation preceding renal damage and identify an EGFRglucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR-deletion protects the animals from HFD-induced endothelial dysfunction, creatininemia and albuminuria. Furthermore, we show that HFD led to marked changes of the aortic transcriptome in WT but not in KO animals, indicative of EGFR-dependent SRF activation, matrix dysregulation and mitochondrial dysfunction, the latter confirmed at the cellular level. Studies at the cellular level revealed that high glucose potentiated EGFR/ErbB2-induced stimulation of SRF activity, enhancing the graded signaling responses to EGF, via the EGFR/ErbB2-ROCK-actin-MRTF-pathway and promoted mitochondrial dysfunction. Conclusions: VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations as the result of a potentiated EGFR/ErbB2-ROCK-MRTF-SRF signaling axis and mitochondrial dysfunction. VSM-EGFR may be a therapeutic target in cases of DMT2-induced renovascular disease. |
URI: | https://opendata.uni-halle.de//handle/1981185920/32201.2 http://dx.doi.org/10.25673/32049.2 |
Open Access: | Open access publication |
License: | (CC BY 4.0) Creative Commons Attribution 4.0 |
Sponsor/Funder: | Deutsche Forschungsgemeinschaft (DFG GE905/19-1 and 2, GE905/24-1) |
Appears in Collections: | Julius-Bernstein-Institut für Physiologie |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Supplementary_table_6 (raw data_RNA-Seq_aorta).xlsx | Next Generation Sequencing data of aortas from mice with or without deletion of the EGFR fed with high or standard fat diet | 8.27 MB | Microsoft Excel XML | View/Open |
Supplementary_table_7 (raw data_RNA-Seq_kidney).xlsx | Next Generation Sequencing data of kidneys from mice with or without deletion of the EGFR fed with high or standard fat diet | 4.17 MB | Microsoft Excel XML | View/Open |
Supplementary_table_6 (raw data_RNA-Seq_aorta).csv | CSV copy | 3.12 MB | CSV | View/Open |
Supplementary_table_7 (raw data_RNA-Seq_kidney).csv | CSV copy | 2.12 MB | CSV | View/Open |
Supplementary_table_1A (WT_SFD-vs-WT_HFD_up).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of upregulated genes (NGS analysis) from aortae of wild type mice fed either with standard fat diet or high fat diet. | 526.63 kB | Microsoft Excel XML | View/Open |
README.txt | README file Old | 1.81 kB | Unknown | View/Open |
Supplementary_table_1B (KO_SFD-vs-KO_HFD_up).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of upregulated genes (NGS analysis) from aortae of knockout mice fed either with standard fat diet or high fat diet. | 17.52 kB | Microsoft Excel XML | View/Open |
Supplementary_table_2A (WT_SFD-vs-WT_HFD_down).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of downregulated genes (NGS analysis) from aortae of wild type mice fed either with standard fat diet or high fat diet. | 598.36 kB | Microsoft Excel XML | View/Open |
Supplementary_table_2B (KO_SFD-vs-KO_HFD_down).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of downregulated genes (NGS analysis) from aortae of knockout mice fed either with standard fat diet or high fat diet. | 17.41 kB | Microsoft Excel XML | View/Open |
Supplementary_table_3A (WT_SFD-vs-WT_HFD_up).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of upregulated genes (NGS analysis) from kidneys of wild type mice fed either with standard fat diet or high fat diet. | 79.7 kB | Microsoft Excel XML | View/Open |
Supplementary_table_3B (KO_SFD-vs-KO_HFD_up).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of upregulated genes (NGS analysis) from kidneys of knockout mice fed either with standard fat diet or high fat diet. | 110.85 kB | Microsoft Excel XML | View/Open |
Supplementary_table_4A (WT_SFD-vs-WT_HFD_down).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of downregulated genes (NGS analysis) from kidneys of wild type mice fed either with standard fat diet or high fat diet. | 34.53 kB | Microsoft Excel XML | View/Open |
Supplementary_table_4B (KO_SFD-vs-KO_HFD_down).xlsx | Results of gene set enrichment (GSEA) and transcription factor binding site (TFBSA) analysis of downregulated genes (NGS analysis) from kidneys of knockout mice fed either with standard fat diet or high fat diet. | 39.68 kB | Microsoft Excel XML | View/Open |
Supplementary_table_1A (WT_SFD-vs-WT_HFD_up)_GOrilla Process.csv | CSV copy | 14.85 kB | CSV | View/Open |
Supplementary_table_1A (WT_SFD-vs-WT_HFD_up)_gProfiler.csv | CSV copy | 158.45 kB | CSV | View/Open |
Supplementary_table_2A (WT_SFD-vs-WT_HFD_down)_all genes.csv | CSV copy | 171.72 kB | CSV | View/Open |
Supplementary_table_2A (WT_SFD-vs-WT_HFD_down)_GOrilla Function.csv | CSV copy | 5.41 kB | CSV | View/Open |
Supplementary_table_2A (WT_SFD-vs-WT_HFD_down)_gProfiler.csv | CSV copy | 394.48 kB | CSV | View/Open |
Supplementary_table_2B (KO_SFD-vs-KO_HFD_down)_mRNA.csv | CSV copy | 2.94 kB | CSV | View/Open |
Supplementary_table_2B (KO_SFD-vs-KO_HFD_down)_gProfiler.csv | CSV copy | 16 B | CSV | View/Open |
Supplementary_table_3A (WT_SFD-vs-WT_HFD_up)_GOrilla Component.csv | CSV copy | 599 B | CSV | View/Open |
Supplementary_table_3A (WT_SFD-vs-WT_HFD_up)_GOrilla Process.csv | CSV copy | 5.06 kB | CSV | View/Open |
Supplementary_table_3A (WT_SFD-vs-WT_HFD_up)_gProfiler.csv | CSV copy | 13.35 kB | CSV | View/Open |
Supplementary_table_3B (KO_SFD-vs-KO_HFD_up)_Pscan.csv | CSV copy | 813 B | CSV | View/Open |
Supplementary_table_3B (KO_SFD-vs-KO_HFD_up)_GOrilla Process.csv | CSV copy | 4.62 kB | CSV | View/Open |
Supplementary_table_3B (KO_SFD-vs-KO_HFD_up)_gProfiler.csv | CSV copy | 36.96 kB | CSV | View/Open |
Supplementary_table_4A (WT_SFD-vs-WT_HFD_down)_gProfiler.csv | CSV copy | 996 B | CSV | View/Open |
Supplementary_table_4B (KO_SFD-vs-KO_HFD_down)_gProfiler.csv | CSV copy | 7.26 kB | CSV | View/Open |
Supplementary_table_1B (KO_SFD-vs-KO_HFD_up)_GOrilla.csv | CSV copy | 15 B | CSV | View/Open |
Supplementary_table_1B (KO_SFD-vs-KO_HFD_up)_gProfiler.csv | CSV copy | 649 B | CSV | View/Open |
Supplementary_table_1A (WT_SFD-vs-WT_HFD_up)_Pscan.csv | CSV copy | 2.45 kB | CSV | View/Open |
Supplementary_table_1A (WT_SFD-vs-WT_HFD_up)_all genes.csv | CSV copy | 171.72 kB | CSV | View/Open |
Supplementary_table_1A (WT_SFD-vs-WT_HFD_up)_GOrilla Function.csv | CSV copy | 1.42 kB | CSV | View/Open |
README.txt | README file | 4.64 kB | Text | View/Open |