title: Protective role of insulin-like growth factor-1 receptor in endothelial cells against unilateral ureteral obstruction-induced renal fibrosis.
abstract: Insulin-like growth factor-1 receptor (IGF-1R) can regulate vascular homeostasis and endothelial function. We studied the role of IGF-1R in oxidative stress-induced endothelial dysfunction. Unilateral ureteral obstruction (UUO) was performed in wild-type (WT) mice and mice with endothelial cell (EC)-specific IGF-1R knockout (KO). After UUO in endothelial IGF-1R KO mice, endothelial barrier dysfunction was more severe than in WT mice, as seen by increased inflammatory cell infiltration and vascular endothelial (VE)-cadherin phosphorylation. UUO in endothelial IGF-1R KO mice increased interstitial fibroblast accumulation and enhanced extracellular protein deposition as compared with the WT mice. Endothelial barrier function measured by transendothelial migration in response to hydrogen peroxide (H2O2) was impaired in ECs. Silencing IGF-1R enhanced the influence of H2O2 in disrupting the VE-protein tyrosine phosphatase/VE-cadherin interaction. Overexpression of IGF-1R suppressed H2O2-induced endothelial barrier dysfunction. Furthermore, by using the piggyBac transposon system, we expressed IGF-1R in VE cells in mice. The expression of IGF-1R in ECs also suppressed the inflammatory cell infiltration and renal fibrosis induced by UUO. IGF-1R KO in the VE-cadherin lineage of bone marrow cells had no significant effect on the UUO-induced fibrosis, as compared with control mice. Our results indicate that IGF-1R in the endothelium maintains the endothelial barrier function by stabilization of the VE-protein tyrosine phosphatase/VE-cadherin complex. Decreased expression of IGF-1R impairs endothelial function and increases the fibrosis of kidney disease.
authors.affiliation: Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Ming
authors.initials: M
authors.lastname: Liang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, and Department of Veterans Affairs, Nashville, Tennessee.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Woodard
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Anlin
authors.initials: A
authors.lastname: Liang
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, and Department of Veterans Affairs, Nashville, Tennessee.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Wilson
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: jizhongc@bcm.edu.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D016133:Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014471:Umbilical Veins; D014517:Ureteral Obstruction
chemical_list: D017526:Receptor, IGF Type 1