Jin Denan, Ueda Haruhiko, Takai Shinji, Okamoto Yukiko, Muramatsu Michiko, Sakaguchi Masato, Shibahara Nobuhisa, Katsuoka Yoji, Miyazaki Mizuo
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
J Am Soc Nephrol. 2005 Apr;16(4):1024-34. doi: 10.1681/ASN.2003121009. Epub 2005 Mar 2.
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-beta1 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-beta-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-, AT(1) receptor-, and TGF-beta-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.
据推测，糜酶可能参与血液透析血管通路功能障碍，因为已知糜酶是一种将血管紧张素I（Ang I）转化为Ang II以及将潜伏的转化生长因子-β1（TGF-β1）转化为活性形式的有效酶。在犬的肱动脉和静脉之间建立动静脉（AV）内瘘。在AV吻合术中，比较静脉侧和动脉侧的管壁时，静脉壁上的偏心性新内膜形成最为明显。与AV吻合术下游的静脉侧相比，在AV吻合术上游的静脉侧发现严重的新内膜增生（内膜/中膜，153±25%）。糜酶和TGF-β阳性肥大细胞明显积聚在增生的新内膜和中膜中。随着糜酶表达的降低，通过NK3201（一种糜酶抑制剂）治疗，Ang II、AT（1）受体和TGF-β阳性区域显著减少，并且该组的新内膜形成（内膜/中膜：区域A，53±9%，P<0.001；区域B，54±14%，P<0.001）也得到显著抑制。尽管赖诺普利治疗在预防新内膜形成方面也有一些有益作用，但其程度小于糜酶抑制。这些发现表明，肥大细胞衍生的糜酶在AV内瘘通路失败的发病机制中起重要作用，并且抑制糜酶可能是临床环境中治疗血液透析血管通路功能障碍的治疗靶点。
