Increased expression of HIF-1alpha, VEGF-A and its receptors, MMP-2, TIMP-1, and ADAMTS-1 at the venous stenosis of arteriovenous fistula in a mouse model with renal insufficiency.
OBJECTIVE
A mouse model of renal insufficiency with arteriovenous fistula (AVF) and venous stenosis was created. The authors tested the hypothesis that there is increased gene expression of hypoxia-inducible factor-1 alpha (HIF-1alpha); vascular endothelial growth factor-A (VEGF-A) and its receptors (VEGFR-1, -2); matrix metalloproteinase-2 (MMP-2), -9 (MMP-9); tissue inhibitor of metalloproteinase-1, -2 (TIMP-1, -2); and a disintegrin and metalloproteinase thrombospondin-1 (ADAMTS-1) at the venous stenosis.


METHODS
Nineteen male C57BL/6 mice underwent a left nephrectomy and a surgical occlusion of the right upper pole to induce renal function characterized in eight animals. Twenty eight days later, an AVF (n = 11) was created from the right carotid artery to ipsilateral jugular vein, and the mice were killed at day 7 (n = 4) and day 14 (n = 4). The outflow and control veins were removed for gene expression. Three mice were killed at day 28 for histologic analysis.


RESULTS
The mean serum blood urea nitrogen level remained significantly elevated for 8 weeks when compared with baseline (P < .05). By day seven, there was a significant increase in the expression of HIF-1alpha, VEGF-A, VEGFR-1, VEGFR-2, MMP-2, TIMP-1, and ADAMTS-1 at the outflow vein, with HIF-1alpha and TIMP-1 levels significantly elevated at day 14 (P < .05). By day 28, the venous stenosis was characterized by a thickened vein wall and neointima.


CONCLUSIONS
A mouse model of renal insufficiency with AVF was developed that had increased expression of HIF-1alpha, VEGF-A, VEGFR-1, VEGFR-2, MMP-2, TIMP-1, and ADAMTS-1 at the outflow vein with venous stenosis by day 28.
Misra
Sanjay
S
Department of Radiology, Mayo Clinic College of Medicine, 200 First Street SW, Alfred 6460, Rochester, MN 55905, USA. misra.sanjay@mayo.edu
Shergill
Uday
U
Yang
Binxia
B
Janardhanan
Rajiv
R
Misra
Khamal D
KD
D051722:ADAM Proteins / Q000235:genetics*; D000071097:ADAMTS1 Protein; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001806:Blood Urea Nitrogen; D002339:Carotid Arteries / Q000601:surgery; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007601:Jugular Veins / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051437:Renal Insufficiency / Q000601:surgery*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C486323:Adamts1 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse