β-Catenin is markedly induced in a murine model of an arteriovenous fistula: The effect of metalloproteinase inhibition

Karl A. Nath, Joseph P. Grande, Lu Kang, Julio P. Juncos, Allan W. Ackerman, Anthony J. Croatt, Zvonimir S. Katusic

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F1270-F1277
JournalAmerican Journal of Physiology - Renal Physiology
Volume299
Issue number6
DOIs
StatePublished - Dec 1 2010

Keywords

  • Glycogen synthase kinase-3β
  • Matrix metalloproteinase-9
  • Neointimal hyperplasia

ASJC Scopus subject areas

  • Physiology
  • Urology

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