title: The role of Iex-1 in the pathogenesis of venous neointimal hyperplasia associated with hemodialysis arteriovenous fistula.
abstract: Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage renal disease worldwide and the majority requires hemodialysis. In the present study, the role of the intermediate early response gene X-1 (IEX-1), also known as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. In Iex-1-/- mice and wild type (WT) controls, chronic kidney disease was induced and an AVF placed 28 days later by connecting the carotid artery to jugular vein. The outflow vein was removed three days following the creation of the AVF and gene expression analysis demonstrated a significant decrease in vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant protein-1 (Mcp-1) gene expression in Iex-1-/- mice when compared to WT mice (P<0.05). At 28 days after AVF placement, histomorphometric and immune-histochemical analyses of the outflow vein demonstrated a significant decrease in neointimal hyperplasia with an increase in average lumen vessel area associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of Iex-1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In aggregate, these results indicate that the absence of IEX-1 gene results in reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of nanoparticles coated with calcitriol reduced Iex-1 and VNH.
authors.affiliation: Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Akshaar
authors.initials: A
authors.lastname: Brahmbhatt
authors.affiliation: Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Evelyn
authors.initials: E
authors.lastname: NievesTorres
authors.affiliation: Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Binxia
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Lab Medicine and Pathology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Edwards
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Prabir
authors.initials: P
authors.lastname: Roy Chaudhury
authors.affiliation: Department of Chemical & Biomolecular Engineering, University of Illinois at Urbana-Champaign, Champaign, Illinois, United States of America.
authors.forename: Min Kyun
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Chemical & Biomolecular Engineering, University of Illinois at Urbana-Champaign, Champaign, Illinois, United States of America.
authors.forename: Hyunjoon
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Biochemistry and Molecular Biology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Biochemistry and Molecular Biology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America; Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America; Department of Biochemistry and Molecular Biology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Misra
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000502:physiology*; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D020100:Hydrogels; D006965:Hyperplasia; D017874:Immediate-Early Proteins / Q000172:deficiency* / Q000502:physiology; D007676:Kidney Failure, Chronic / Q000628:therapy; D019344:Lactic Acid; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000473:pathology; D053758:Nanoparticles; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D006435:Renal Dialysis; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D014680:Veins / Q000473:pathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020100:Hydrogels; C099815:IER3 protein, human; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D020780:Matrix Metalloproteinase 9; D002117:Calcitriol