TGF-BETA-1 IN GLOMERULOSCLEROSIS AND INTERSTITIAL FIBROSIS OF ADRIAMYCIN NEPHROPATHY

The role of transforming growth factor-beta1 (TGF-beta1) for renal injury was investigated in the chronic model of progressive renal disease in rats induced by the injection of adriamycin. The renal cortical tissues were sampled at weeks 4, 8 and 16 for histological examination, either cortical or glomerular cell culture, and RNA extraction. A progressive increase in fibronectin synthesis was found in metabolically labeled cortical or glomerular culture at week 8 or 16, correlating with the degree of glomerulosclerosis and interstitial fibrosis. TGF-beta bioassay (mink lung epithelial cell assay) showed a progressive increase in latent TGF-beta secretion from cortex and glomeruli, while the amount of active TGF-beta was small. The peak of latent TGF-beta levels at week 16 coincided with the intense TGF-beta1 staining of inflammatory cells dispersed in the interstitium and glomeruli. Northern blotting demonstrated the difference in the mRNA expression patterns of TGF-beta1 and latent TGF-beta1 binding protein (LTBP) in the cortex. TGF-beta1 mRNA was constantly high throughout the experiment, while LTBP mRNA increased progressively and reached a peak at week 16. Furthermore, mRNA levels of fibronectin, procollagen alpha2(I), and TGF-beta type II and type III receptors increased progressively in a similar pattern to the renal histological changes. These temporal and spacial relationships between the renal histological changes and the increased expression of TGF-beta1 and TGF-beta receptors may thus suggest that TGF-beta1 plays an important role in the process of the renal fibrosis and sclerosis.