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Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

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Název: Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo
Autoři: Christian Stern, Barbara Schreier, Alexander Nolze, Sindy Rabe, Sigrid Mildenberger, Michael Gekle
Zdroj: Diabetologia
Informace o vydavateli: Springer Science and Business Media LLC, 2020.
Rok vydání: 2020
Témata: 0301 basic medicine, Serum Response Factor, Myocytes, Smooth Muscle, Vascular Remodeling, Diet, High-Fat, Article, Muscle, Smooth, Vascular, Cell Line, Mice, 03 medical and health sciences, Animals, Humans, Diabetic Nephropathies, Obesity, Aorta, Mice, Knockout, 2. Zero hunger, ddc:610, 0303 health sciences, Actins, 3. Good health, ErbB Receptors, HEK293 Cells, Aorta/metabolism [MeSH], Diabetic Nephropathies/metabolism [MeSH], Epidermal growth factor receptor, Diabetes Mellitus, Type 2/physiopathology [MeSH], Cell Line [MeSH], Aorta/physiopathology [MeSH], Muscle, Smooth, Vascular/physiopathology [MeSH], Hyperglycemia/physiopathology [MeSH], Diabetic Angiopathies/metabolism [MeSH], Vascular dysfunction, Diabetic Nephropathies/genetics [MeSH], Obesity/metabolism [MeSH], Obesity/physiopathology [MeSH], Renal damage, Myocytes, Smooth Muscle [MeSH], Diabetes mellitus, Humans [MeSH], ErbB Receptors/genetics [MeSH], Muscle, Smooth, Vascular/metabolism [MeSH], rho-Associated Kinases/metabolism [MeSH], Animals [MeSH], Diabetic Angiopathies/physiopathology [MeSH], Diet, High-Fat [MeSH], Mice, Knockout [MeSH], Diabetic Nephropathies/physiopathology [MeSH], Mice [MeSH], Serum response factor, Hyperglycemia/metabolism [MeSH], HEK293 Cells [MeSH], Serum Response Factor/metabolism [MeSH], Vascular Remodeling [MeSH], Actins/metabolism [MeSH], Signal Transduction [MeSH], Diabetic Angiopathies/genetics [MeSH], Diabetes Mellitus, Type 2/metabolism [MeSH], EGFR, Diabetes Mellitus, Type 2, Hyperglycemia, Diabetic Angiopathies, Signal Transduction
Popis: Aims/hypothesis Obesity causes type 2 diabetes 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 obesity-induced renovascular dysfunction, as well as EGFR–hyperglycaemia crosstalk. Methods The role of VSM-EGFR during high-fat diet (HFD)-induced type 2 diabetes was investigated in a mouse model with inducible, VSM-specific EGFR-knockout (KO). Various structural and functional variables as well as transcriptome changes, in vivo and ex vivo, were assessed. The impact of hyperglycaemia on EGFR-induced signalling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results We show that VSM-EGFR mediates obesity/type 2 diabetes-induced vascular dysfunction, remodelling and transcriptome dysregulation preceding renal damage and identify an EGFR–glucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR deletion protects the animals from HFD-induced endothelial dysfunction, creatininaemia and albuminuria. Furthermore, we show that HFD leads to marked changes of the aortic transcriptome in wild-type 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/EGF receptor 2 (ErbB2)-induced stimulation of SRF activity, enhancing the graded signalling responses to EGF, via the EGFR/ErbB2–ROCK–actin–MRTF pathway and promoted mitochondrial dysfunction. Conclusions/interpretation VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations. We propose that a potentiated EGFR/ErbB2–ROCK–MRTF–SRF signalling axis and mitochondrial dysfunction underlie the role of EGFR. This advanced working hypothesis will be investigated in mechanistic depth in future studies. VSM-EGFR may be a therapeutic target in cases of type 2 diabetes-induced renovascular disease. Data availability The datasets generated during and/or analysed during the current study are available in: (1) share_it, the data repository of the academic libraries of Saxony-Anhalt (10.25673/32049.2); and (2) in the gene expression omnibus database with the study identity GSE144838 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144838).
Druh dokumentu: Article
Other literature type
Popis souboru: application/pdf
Jazyk: English
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-020-05187-4
DOI: 10.25673/38243
Přístupová URL adresa: https://link.springer.com/content/pdf/10.1007/s00125-020-05187-4.pdf
https://pubmed.ncbi.nlm.nih.gov/32548701
https://link.springer.com/article/10.1007/s00125-020-05187-4
https://link.springer.com/content/pdf/10.1007/s00125-020-05187-4.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476975
https://www.scilit.net/article/c51b7abf74983e6f379a3c2caad16beb?action=show-references
https://pubmed.ncbi.nlm.nih.gov/32548701/
https://opendata.uni-halle.de/handle/1981185920/38486?locale=de
https://repository.publisso.de/resource/frl:6469026
Rights: CC BY
Přístupové číslo: edsair.doi.dedup.....cce0da8cc0209710723cbc450e03a3bc
Databáze: OpenAIRE
Popis
Abstrakt:Aims/hypothesis Obesity causes type 2 diabetes 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 obesity-induced renovascular dysfunction, as well as EGFR–hyperglycaemia crosstalk. Methods The role of VSM-EGFR during high-fat diet (HFD)-induced type 2 diabetes was investigated in a mouse model with inducible, VSM-specific EGFR-knockout (KO). Various structural and functional variables as well as transcriptome changes, in vivo and ex vivo, were assessed. The impact of hyperglycaemia on EGFR-induced signalling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results We show that VSM-EGFR mediates obesity/type 2 diabetes-induced vascular dysfunction, remodelling and transcriptome dysregulation preceding renal damage and identify an EGFR–glucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR deletion protects the animals from HFD-induced endothelial dysfunction, creatininaemia and albuminuria. Furthermore, we show that HFD leads to marked changes of the aortic transcriptome in wild-type 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/EGF receptor 2 (ErbB2)-induced stimulation of SRF activity, enhancing the graded signalling responses to EGF, via the EGFR/ErbB2–ROCK–actin–MRTF pathway and promoted mitochondrial dysfunction. Conclusions/interpretation VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations. We propose that a potentiated EGFR/ErbB2–ROCK–MRTF–SRF signalling axis and mitochondrial dysfunction underlie the role of EGFR. This advanced working hypothesis will be investigated in mechanistic depth in future studies. VSM-EGFR may be a therapeutic target in cases of type 2 diabetes-induced renovascular disease. Data availability The datasets generated during and/or analysed during the current study are available in: (1) share_it, the data repository of the academic libraries of Saxony-Anhalt (10.25673/32049.2); and (2) in the gene expression omnibus database with the study identity GSE144838 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144838).
ISSN:14320428
0012186X
DOI:10.1007/s00125-020-05187-4