Open Accessβ-Catenin is markedly induced in a murine model of an arteriovenous fistula: the effect of metalloproteinase inhibition
Author(s) -
Karl A. Nath,
Joseph P. Grande,
Kang Lu,
Julio P. Juncos,
Allan W. Ackerman,
Anthony J. Croatt,
Zvonimir S. Katušić
Publication year - 2010
Publication title -
american journal of physiology. renal physiology./american journal of physiology. renal physiology
Language(s) - English
Resource type - Journals
eISSN - 1931-857X
pISSN - 1522-1466
DOI - 10.1152/ajprenal.00488.2010
Subject(s) - downregulation and upregulation , catenin , gsk 3 , gsk3b , proliferating cell nuclear antigen , cancer research , integrin linked kinase , neointimal hyperplasia , rho associated protein kinase , medicine , microbiology and biotechnology , kinase , pathology , chemistry , biology , signal transduction , immunohistochemistry , protein kinase a , wnt signaling pathway , cyclin dependent kinase 2 , biochemistry , restenosis , stent , gene
Neointimal hyperplasia contributes to failure of hemodialysis arteriovenous fistulas (AVFs). Increased expression of matrix metalloproteinase (MMP)-9 occurs in AVFs, and MMP-9 is implicated in neointimal hyperplasia and vascular injury. Recent studies demonstrate that MMP-9, by degrading N-cadherin, leads to increased expression of β-catenin and β-catenin-dependent proliferation of smooth muscle cells. The present study examined this pathway in the venous limb of a murine AVF model. Western analyses demonstrate that, in this model, there is diminished expression of N-cadherin accompanied by increased expression of β-catenin, c-Myc, and proliferating cell nuclear antigen (PCNA). By immunohistochemistry, β-catenin and c-Myc localized to proliferating smooth muscle cells in the venous limb of the AVF. Increased expression of β-catenin was accompanied by augmented expression of phosphorylated (p)-glycogen synthase kinase (GSK)-3β, GSK-3β, and integrin-linked kinase. The administration of doxycycline suppressed MMP-9 expression but did not reduce venous histological injury in the AVF, or increase AVF patency assessed 6 wk after its creation. Doxycycline did not influence expression of β-catenin, c-Myc, GSK-3β, or integrin-linked kinase. Thus, in this vascular injury model, the upregulation of β-catenin cannot be readily attributed to MMP-9 upregulation; increased β-catenin expression may reflect either the upregulation of p-GSK-3β, GSK-3β, or integrin-linked kinase. This study provides the first exploration of β-catenin in an AVF, demonstrating substantial upregulation of this mitogenic signaling molecule and uncovering possible mechanisms that may account for such upregulation.