两肾一夹型高血压大鼠中氨肽酶A的肾脏表达

Renal expression of aminopeptidase A in rats with two-kidney, one-clip hypertension.

作者信息

Wolf G, Wenzel U, Assmann K J, Stahl R A

机构信息

Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Hamburg, Germany.

出版信息

Nephrol Dial Transplant. 2000 Dec;15(12):1935-42. doi: 10.1093/ndt/15.12.1935.

DOI:10.1093/ndt/15.12.1935

PMID:11096137

Abstract

BACKGROUND

Angiotensin II (ANG II) is a major factor involved in the progression of chronic renal disease. Although the generation of this vasoactive peptide has been investigated in great detail, only a few studies have hitherto addressed the metabolism of ANG II into fragments such as angiotensin III and IV (ANG III, IV) which may exert physiological effects independent of ANG II. Aminopeptidase A (APA) is the major enzyme degrading ANG II. The aim of the current study was to evaluate glomerular APA expression in rats with two-kidney, one-clip hypertension.

METHODS

The left renal artery was restricted with a 0.2-mm silver clip. Kidneys were harvested 1 and 4 weeks after surgery. APA enzyme and protein expression was evaluated in kidney sections. Total APA enzyme activity and mRNA expression was assessed in isolated glomeruli. Degradation of exogenous ANG II by isolated glomeruli was measured with reverse-phase high-performance liquid chromatography.

RESULTS

APA enzyme activity, protein, and mRNA expression were stimulated in the clipped kidney 1 week after surgery compared with the contralateral kidney or normal controls. In contrast, 4 weeks after clipping APA activity and expression was higher in the contralateral kidney. In parallel to these findings, degradation of ANG II was greatest in isolated glomeruli obtained from the clipped kidney after 1 week. However, preparations from the contralateral kidney 4 weeks after surgery were more active in the metabolism of exogenous ANG II.

CONCLUSION

The present study provides evidence that APA is complexly regulated in in vivo situations with an activated local renin-ANG II system. ANG II appears to play a direct role in this regulation. However, since conversion of ANG II to ANG III by APA is the initial step leading to the formation of ANG IV which may exert detrimental effects not mediated through classical ANG II receptors, a local increase in APA activity may contribute to the progression of chronic renal disease even during complete AT(1)-receptor blockade.

摘要

背景

血管紧张素II（ANG II）是参与慢性肾病进展的主要因素。尽管对这种血管活性肽的生成已进行了详细研究，但迄今为止，仅有少数研究探讨了ANG II代谢为诸如血管紧张素III和IV（ANG III、IV）等片段的过程，这些片段可能发挥独立于ANG II的生理作用。氨肽酶A（APA）是降解ANG II的主要酶。本研究的目的是评估两肾一夹高血压大鼠肾小球APA的表达。

方法

用0.2毫米银夹夹闭左肾动脉。术后1周和4周采集肾脏。评估肾切片中APA酶和蛋白的表达。在分离的肾小球中评估总APA酶活性和mRNA表达。用反相高效液相色谱法测定分离的肾小球对外源性ANG II的降解。

结果

与对侧肾脏或正常对照相比，术后1周夹闭侧肾脏的APA酶活性、蛋白和mRNA表达增加。相反，夹闭4周后，对侧肾脏的APA活性和表达更高。与这些发现一致，术后1周从夹闭侧肾脏获得的分离肾小球中ANG II的降解最大。然而，术后4周对侧肾脏的制剂对外源性ANG II的代谢更活跃。

结论

本研究提供了证据表明，在局部肾素-ANG II系统激活的体内情况下，APA受到复杂调节。ANG II似乎在这种调节中起直接作用。然而，由于APA将ANG II转化为ANG III是导致ANG IV形成的第一步，ANG IV可能发挥不通过经典ANG II受体介导的有害作用，因此即使在完全阻断AT(1)受体期间，APA活性的局部增加也可能促进慢性肾病的进展。