Severe proteinuria, sustained for 6 months, induces tubular epithelial cell injury and cell filtration in rats but not progressive interstitial fibrosis

Background. Sustained proteinuria is reported to be very harmful to the tub ulointerstitium, leading to severe interstitial injury. However, it remains unclear whether sustained proteinuria itself is responsible for severe int erstitial injury because, in the previously reported models, the developmen t 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 (m Ab) 5-1-6 twice a week for 6 months and were then sacrificed. Results. mAb 5-1-6 induced massive proteinuria in II rats. In nine rats wit h mild proteinuria, no histological alteration could be detected with light microscopy and immunofluorescence. In nephrotic rats, light microscopy sho wed minor glomerular abnormalities, with interstitial oedema, tubular epith elial cell degeneration and interstitial cell infiltration. Immunofluoresce nce revealed increased expression of vimentin and an increased number of OX 1-, OX19- and ED1-positive cells. However, we could not detect any accumula tion 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 wit hout severe glomerular abnormalities, nephrectomy or other manoeuvres known to induce disturbed haemodynamics, using an agent without tubulointerstiti al toxicity, and considered it to be suitable for investigating the direct toxicity of proteinuria. In this model, isolated massive proteinuria induce d interstitial injury. However, the degree of injury was suggested to be mu ch less than that observed in other previously developed models.