PROTEIN RESTRICTION REDUCES TRANSFORMING GROWTH-FACTOR-BETA AND INTERSTITIAL FIBROSIS IN NEPHROTIC SYNDROME

Nephrotic syndrome induced by puromycin aminonucleoside (PAN) is chara cterized by tubulointerstitial (TI) inflammation, foci of TI fibrosis, and increased renal mRNA levels for matrix genes, the tissue inhibito r of metalloproteinases (TIMP), and the transforming growth factor-bet a 1 (TGF-beta 1). To investigate the ability of a low-protein diet kno wn to decrease TI inflammation to alter the degree of renal fibrosis, we studied four groups of rats: 27% protein PAN, 27% protein control, 8% protein PAN, and 8% protein control. Penal TGF-beta 1 mRNA levels c orrelated with the number of interstitial macrophages (r = 0.76) and w ere significantly reduced by dietary protein restriction. On day 10, N orthern blot analysis showed that the elevated renal mRNA levels for p rocollagens alpha 1(I), alpha 1(III), and alpha 2(IV) and fibronectin in the PAN-treated rats were significantly reduced by 8% dietary prote in. In contrast, genes regulating matrix degradation (stromelysin and TIMP) were relatively unchanged by the low-protein diet. The number of foci of interstitial fibrosis and total renal collagen were greater i n the PAN + 27% protein group than in the control groups. Both paramet ers of fibrosis were partially normalized in the PAN + 8% protein grou p. The results of this study suggest that dietary protein restriction attenuates TI fibrosis in PAN-induced nephrosis by partially reversing the increase in renal matrix synthesis. This effect was associated wi th decreased renal expression of the fibrogenic cytokine TGF-beta 1, w hich may be partially mediated by the concomitant reduction in the num ber of interstitial inflammatory macrophages.