title: Glucose-induced endothelin-1 expression is regulated by ERK5 in the endothelial cells and retina of diabetic rats.
abstract: Upregulation of endothelin 1 (ET-1) causing blood flow alteration and increased extracellular matrix production are characteristic features of diabetic angiopathy. Several glucose-induced signaling mechanisms cause ET-1 upregulation in diabetic angiopathy. Extracellular signal-regulated kinase 5 (ERK5) is a member of the MAPK family, which plays a key role in cardiovascular development. ERK kinase (MEK) 5 is the specific MEK for ERK5 activation. In this study we examined the role of glucose-induced ERK5 signaling in mediating ET-1 expression in diabetic angiopathy. We investigated retinas from 1-month STZ-induced diabetic rats and human macro- and microvascular endothelial cells to study ERK5-dependent ET-1 alterations. Glucose (25 mmol/L) caused significant upregulation of ET-1 mRNA and downregulation of ERK5 and Kruppel-like factor 2 (KLF2) after 24 h treatment in the endothelial cells. Simultaneously, phospho-ERK5 proteins were reduced. Activation of ERK5 by constitutively active MEK5 (caMEK5) upregulated KLF2 and suppressed ET-1 expression in both cell lines, whereas ERK5 siRNA transfection resulted in decreased ERK5 and KLF2 and increased ET-1 mRNA expression. In addition, caMEK5 prevented glucose-induced upregulation of ET-1. Furthermore, 1 month of diabetes caused a significant increase in retinal ET-1 mRNA and decrease in ERK5 mRNA expression. These data indicate that ERK5 signaling regulates glucose-induced ET-1 expression in diabetes. The ERK5/ET-1 pathway may provide a potential novel target for the treatment of diabetic angiopathy.
authors.affiliation: Department of Pathology, University of Western Ontario, Schulich School of Medicine & Dentistry, London, ON N6A 5A5, Canada.
authors.forename: Yuexiu
authors.initials: Y
authors.lastname: Wu
authors.forename: Biao
authors.initials: B
authors.lastname: Feng
authors.forename: Shali
authors.initials: S
authors.lastname: Chen
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zuo
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D048671:MAP Kinase Kinase 5 / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D019332:Endothelin-1; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D034741:RNA, Small Interfering; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; D005947:Glucose