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Effect of Chymase Inhibition on the Arteriovenous Fistula Stenosis in Dogs

Denan Jin^*, Haruhiko Ueda, Shinji Takai^*, Yukiko Okamoto^*, Michiko Muramatsu^*, Masato Sakaguchi^*, Nobuhisa Shibahara, Yoji Katsuoka and Mizuo Miyazaki^*

Departments of ^* Pharmacology and Urology, Osaka Medical College, Osaka, Japan

Address correspondence to: Dr. Denan Jin, Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. Phone: +81-72-684-6418; Fax: +81-72-684-6518; E-mail: pha012{at}art.osaka-med.ac.jp

Received for publication December 9, 2003. Accepted for publication January 21, 2005.

It was hypothesized that chymase may participate in hemodialysis vascular access dysfunction, as chymase has been known to be an effective enzyme in the conversion of angiotensin I (Ang I) to Ang II and in the latent TGF-1 to the active form. An arteriovenous (AV) fistula was created between the brachial artery and vein in dogs. In the AV anastomosis, when the walls of the venous and arterial sides were compared, the eccentric neointimal formation was most evident in the venous wall. Compared with the venous side downstream of the AV anastomosis, a severe neointimal hyperplasia was found in the venous side upstream of the AV anastomosis (intima/media, 153 ± 25%). The chymase- and TGF-–positive mast cells were markedly accumulated in the proliferous neointima and media. In association with the reduction of chymase expression, a marked decrease in Ang II–, AT₁ receptor–, and TGF-–positive areas was achieved by NK3201 (a chymase inhibitor) treatment, and the neointima formation (intima/media: region A, 53 ± 9%, P < 0.001; region B, 54 ± 14%, P < 0.001) was also significantly suppressed in this group. Although lisinopril treatment also provided some beneficial effects with regard to the prevention of neointimal formation, the degree was less than that seen with chymase inhibition. These findings indicate that mast cell–derived chymase plays an essential role in the pathogenesis of the AV fistula access failure and that chymase inhibition may be a therapeutic target for the treatment of hemodialysis vascular access dysfunction in clinic settings.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673