Protein restriction reduces transforming growth factor-beta and interstitial fibrosis in nephrotic syndrome

Nephrotic syndrome induced by puromycin aminonucleoside (PAN) is characterized by tubulointerstitial (TI) inflammation, foci of TI fibrosis, and increased renal mRNA levels for matrix genes, the tissue inhibitor of metalloproteinases (TIMP), and the transforming growth factor-beta 1 (TGF-beta 1). To investigate the ability of a low-protein diet known 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. Renal TGF-beta 1 mRNA levels correlated with the number of interstitial macrophages (r = 0.76) and were significantly reduced by dietary protein restriction. On day 10, Northern blot analysis showed that the elevated renal mRNA levels for procollagens alpha 1 (I), alpha 1(III), and alpha 2(IV) and fibronectin in the PAN-treated rats were significantly reduced by 8% dietary protein. 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 in the PAN + 27% protein group than in the control groups. Both parameters of fibrosis were partially normalized in the PAN + 8% protein group. 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 with decreased renal expression of the fibrogenic cytokine TGF-beta 1, which may be partially mediated by the concomitant reduction in the number of interstitial inflammatory macrophages.