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.