title: A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1.
abstract: The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Lu
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.affiliation: Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota;
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hillestad
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.affiliation: Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
authors.affiliation: Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; nath.karl@mayo.edu.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
mesh_terms: D000743:Anemia, Hemolytic / Q000150:complications* / Q000378:metabolism / Q000628:therapy; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D000229:Dependovirus; D005240:Feasibility Studies; D015316:Genetic Therapy; D006130:Growth Disorders / Q000150:complications* / Q000378:metabolism / Q000628:therapy; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000150:complications* / Q000378:metabolism / Q000628:therapy; D008297:Male; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009942:Organometallic Compounds; D011183:Postoperative Complications / Q000209:etiology* / Q000378:metabolism / Q000628:therapy; D015854:Up-Regulation
chemical_list: D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D051547:Heme Oxygenase-1
keywords: arteriovenous fistula; chronic kidney disease; heme oxygenase-1; murine model