在肾血管性高血压的缺血肾脏中，糜酶产生的不依赖血管紧张素转换酶的血管紧张素II生成上调。

Angiotensin converting enzyme-independent angiotensin ii production by chymase is up-regulated in the ischemic kidney in renovascular hypertension.

作者信息

Sadjadi Javid, Kramer Gerald L, Yu Chun-Hua, Burress Welborn M, Chappell Mark C, Gregory Modrall J

机构信息

Department of Surgery, Division of Vascular Surgery, Dallas Veterans Affairs Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

出版信息

J Surg Res. 2005 Aug;127(2):65-9. doi: 10.1016/j.jss.2005.02.031.

DOI:10.1016/j.jss.2005.02.031

PMID:15869764

Abstract

BACKGROUND

Tissue angiotensin II (ANG II) levels are elevated in both kidneys in renovascular hypertension (RVH). It has been demonstrated previously that intrarenal ANG II is augmented by an angiotensin converting enzyme (ACE) dependent mechanism in the non-ischemic kidney, but the role of ACE-independent production of ANG II in the kidney by the enzyme chymase is unknown. This study tested the hypothesis that intrarenal chymase activity is up-regulated in RVH.

METHODS

A two-kidney, one-clip (2K1C) rat model was used to induce RVH (n = 6 rats/group). Regulation of intrarenal chymase activity by plasma ANG II was investigated using an ANG II-infusion model. At sacrifice 14 days post-operatively, steady-state ANG II levels in plasma and kidney were quantified by radioimmunoassay. ANG II production was quantified in kidney homogenates by incubating at 37 degrees C for 60 min with enzyme substrate (200 microm ANG I) alone or substrate containing the chymase inhibitor chymostatin. ANG II was separated and quantitated by HPLC. Chymase activity was defined as the fraction of ANG II production inhibited by Chymostatin.

RESULTS

2K1C and ANG II-infused rats developed significant hypertension, compared to control rats (P = 0.0001 and P = 0.001, respectively). Chymase-dependent ANG II production was increased in the ischemic kidney, but not the non-ischemic kidney, of 2K1C rats compared to control animals (*P < 0.05). Intrarenal chymase activity was unchanged by ANG II infusion (P = NS).

CONCLUSIONS

Chymase activity is up-regulated in the ischemic kidney of 2K1C rats. Plasma ANG II does not appear to regulate intrarenal chymase activity, suggesting that ischemia per se up-regulates chymase activity in the kidney. ACE-independent ANG II production by chymase may provide a mechanism for augmenting intrarenal ANG II in the ischemic kidney in RVH.

摘要

背景

肾血管性高血压（RVH）时双侧肾脏组织血管紧张素II（ANG II）水平均升高。先前已证实，在非缺血性肾脏中，肾内ANG II通过血管紧张素转换酶（ACE）依赖性机制增加，但由糜酶产生的不依赖ACE的肾内ANG II的作用尚不清楚。本研究检验了RVH时肾内糜酶活性上调的假说。

方法

采用双肾单夹（2K1C）大鼠模型诱导RVH（每组6只大鼠）。使用ANG II输注模型研究血浆ANG II对肾内糜酶活性的调节。术后14天处死时，通过放射免疫分析法对血浆和肾脏中的稳态ANG II水平进行定量。通过在37℃下与酶底物（200μM ANG I）单独孵育或与含有糜酶抑制剂抑糜酶肽的底物孵育来定量肾脏匀浆中的ANG II产生。通过高效液相色谱法分离和定量ANG II。糜酶活性定义为抑糜酶肽抑制的ANG II产生分数。