抗体诱导的Thy-1.1转基因小鼠白蛋白尿和局灶性肾小球硬化加速

Antibody-induced albuminuria and accelerated focal glomerulosclerosis in the Thy-1.1 transgenic mouse.

作者信息

Assmann Karel J M, van Son Jacco P H F, Dïjkman Henry B P M, Mentzel Stef, Wetzels Jack F M

机构信息

Department of Pathology, Division of Nephrology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

出版信息

Kidney Int. 2002 Jul;62(1):116-26. doi: 10.1046/j.1523-1755.2002.00428.x.

DOI:10.1046/j.1523-1755.2002.00428.x

PMID:12081570

Abstract

BACKGROUND

Podocytes play an important role in the development of proteinuria and focal glomerulosclerosis. Previously we have demonstrated that a combination of two monoclonal antibodies (mAb) against aminopeptidase A (APA), an enzyme present on podocytes, induces a massive acute albuminuria in mice. The present study examined the relationship between the acute antibody-induced albuminuria and the development of focal glomerulosclerosis in the Thy-1.1 transgenic mouse. This mouse expresses a hybrid human-mouse Thy-1.1 antigen on the podocytes, and slowly but spontaneously develops albuminuria and focal glomerulosclerosis.

METHODS

Five-week-old non-albuminuric Thy-1.1 transgenic and non-transgenic control mice were injected with anti-APA and anti-Thy-1.1 mAb or saline. Albuminuria was measured at days 1, 7, 14 and 21. At day 21 kidneys were processed for light microscopy, immunofluorescence, and electron microscopy.

RESULTS

Injection of anti-APA and anti-Thy1.1 mAb in Thy-1.1 transgenic mice induced an albuminuria at day 1 that persisted at day 21. The acute albuminuria after injection of anti-APA mAb was more prominent but transient in non-transgenic mice. In non-trangenic mice no albuminuria could be induced with anti-Thy 1.1 mAb. Light microscopy revealed normal glomeruli at day 1 in all transgenic mice, however, at day 21 advanced glomerulosclerotic lesions were seen in mice injected with either anti-APA mAb (37+/-19% of glomeruli affected) or anti-Thy-1.1 mAb (71+/-5%). Non-transgenic mice did not reveal sclerotic lesions at any time investigated. In the transgenic mice the percentage of focal glomerulosclerosis at day 21 did not correlate with albuminuria at day 21. However, we found a highly significant correlation between percentage of focal glomerulosclerosis and the time-averaged albuminuria over the three-week study period (P < 0.001).

CONCLUSION

Injection of a combination of anti-APA or anti-Thy-1.1 mAb into one mo old, non-albuminuric Thy-1.1 transgenic mice induces an acute albuminuria at day 1 that is accompanied by an accelerated focal glomerulosclerosis at day 21. We suggest that the Thy-1.1 transgenic mouse is an excellent model to study specifically the relation between podocytic injury, albuminuria and the development of focal glomerulosclerosis.

摘要

背景

足细胞在蛋白尿和局灶性肾小球硬化的发生发展中起重要作用。此前我们已证明，针对足细胞上存在的一种酶——氨肽酶A（APA）的两种单克隆抗体（mAb）联合使用，可在小鼠中诱导大量急性蛋白尿。本研究在Thy-1.1转基因小鼠中检测了急性抗体诱导的蛋白尿与局灶性肾小球硬化发生之间的关系。这种小鼠在足细胞上表达一种人鼠杂交的Thy-1.1抗原，并缓慢但自发地发展为蛋白尿和局灶性肾小球硬化。

方法

给5周龄无蛋白尿的Thy-1.1转基因小鼠和非转基因对照小鼠注射抗APA和抗Thy-1.1 mAb或生理盐水。在第1、7、14和21天测量蛋白尿。在第21天，对肾脏进行光镜、免疫荧光和电镜检查。

结果

在Thy-1.1转基因小鼠中注射抗APA和抗Thy1.1 mAb在第1天诱导出蛋白尿，并持续至第21天。在非转基因小鼠中，注射抗APA mAb后急性蛋白尿更明显但为短暂性。在非转基因小鼠中，抗Thy 1.1 mAb不能诱导出蛋白尿。光镜检查显示，所有转基因小鼠在第1天肾小球正常，然而，在第21天，注射抗APA mAb（37±19%的肾小球受影响）或抗Thy-1.1 mAb（71±5%）的小鼠出现了进展性肾小球硬化病变。在任何研究时间点，非转基因小鼠均未出现硬化病变。在转基因小鼠中，第21天局灶性肾小球硬化的百分比与第21天的蛋白尿不相关。然而，我们发现局灶性肾小球硬化的百分比与为期三周的研究期间的时间平均蛋白尿之间存在高度显著的相关性（P<0.001）。