Severe proteinuria, sustained for 6 months, induces tubular epithelial cell injury and cell infiltration in rats but not progressive interstitial fibrosis.
Severe proteinuria, sustained for 6 months, induces tubular epithelial cell injury and cell infiltration in rats but not progressive interstitial fibrosis.
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DOI：
10.1093/ndt/15.6.799
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发表时间：
2000-06
期刊：
影响因子：
--
通讯作者：
H. Kikuchi;H. Kawachi;Yumi Ito;K. Matsui;Hitonari Nosaka;A. Saito;M. Orikasa;M. Arakawa;F. Shimizu
中科院分区：
文献类型：
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作者：
H. Kikuchi;H. Kawachi;Yumi Ito;K. Matsui;Hitonari Nosaka;A. Saito;M. Orikasa;M. Arakawa;F. Shimizu
背景：据报道，持续性蛋白尿对小管间质非常有害，可导致严重的间质损伤。然而，目前尚不清楚是否持续性蛋白尿本身是造成严重间质损伤的原因，因为在先前报道的模型中，不能完全排除小管间质病变中除蛋白尿外的其他因素的发生。方法20只大鼠在诱导小鼠免疫球蛋白免疫耐受后，每周2次注射抗大鼠狭缝隔膜单克隆抗体（mAb） 5-1-6，连续6个月后处死。结果mAb 5-1-6诱导11只大鼠出现大量蛋白尿。9只轻度蛋白尿大鼠，光镜和免疫荧光均未见组织学改变。肾病大鼠光镜显示肾小球轻微异常，间质水肿，小管上皮细胞变性，间质细胞浸润。免疫荧光显示波形蛋白表达增加，OX1-、OX19-和ed1阳性细胞数量增加。然而，我们在小管间质中未检测到任何I型和IV型胶原或层粘连蛋白的积累。RT-PCR结果显示，与对照组相比，ⅰ型胶原mRNA的表达没有增加。结论：我们成功地建立了一个没有严重肾小球异常、肾切除术或其他已知会引起血流动力学紊乱的方法的持续性肾病模型，使用了一种没有小管间质毒性的药物，并认为它适合于研究蛋白尿的直接毒性。在这个模型中，分离的大量蛋白尿引起间质损伤。然而，损伤程度被认为比在其他先前开发的模型中观察到的要小得多。
BACKGROUND Sustained proteinuria is reported to be very harmful to the tubulointerstitium, leading to severe interstitial injury. However, it remains unclear whether sustained proteinuria itself is responsible for severe interstitial injury because, in the previously reported models, the development of factors other than proteinuria in tubulointerstitial lesions could not be excluded completely. METHODS After treatment to induce immune tolerance to mouse immunoglobulin, 20 rats were injected with anti-rat slit diaphragm monoclonal antibody (mAb) 5-1-6 twice a week for 6 months and were then sacrificed. RESULTS mAb 5-1-6 induced massive proteinuria in 11 rats. In nine rats with mild proteinuria, no histological alteration could be detected with light microscopy and immunofluorescence. In nephrotic rats, light microscopy showed minor glomerular abnormalities, with interstitial oedema, tubular epithelial cell degeneration and interstitial cell infiltration. Immunofluorescence revealed increased expression of vimentin and an increased number of OX1-, OX19- and ED1-positive cells. However, we could not detect any accumulation of type I and IV collagen or laminin in the tubulointerstitium. RT-PCR showed that the expression of mRNA for type I collagen was not increased, compared with that in control rats. CONCLUSIONS We succeeded in developing a model of persistent nephrosis without severe glomerular abnormalities, nephrectomy or other manoeuvres known to induce disturbed haemodynamics, using an agent without tubulointerstitial toxicity, and considered it to be suitable for investigating the direct toxicity of proteinuria. In this model, isolated massive proteinuria induced interstitial injury. However, the degree of injury was suggested to be much less than that observed in other previously developed models.