Short- or long-term effects of a low-protein diet on fibronectin and transforming growth factor-beta synthesis in Adriamycin-induced nephropathy

Abstract

Increased synthesis and gene expression of fibronectin or transforming growth factor-beta (TGF-beta) have been reported to be involved in the progressive process of doxorubicin hydrochloride (Adriamycin)-induced nephropathy. In the present study, the effects of dietary protein restriction on the synthesis and gene expression of fibronectin or TGF-beta were investigated by immunoprecipitation, Northern blotting, and TGF-beta bioassay in this model after subjects were given either short- or long-term low-protein diets. In the long-term diet experiment, either a normal protein diet (NPD, 20%) or low-protein diet (LPD, 5%) was fed to the Adriamycin rats for 8 weeks after the injection of Adriamycin. An 8-week LPD significantly ameliorated kidney destruction and remarkably reduced the fibronectin synthesis. Furthermore, the significant decreases of the latent TGF-beta secretion and the expression of TGF-beta 1 mRNA were observed in the Adriamycin rats fed an 8-week LPD. In the short-term diet experiment, an NPD or LPD was fed to the Adriamycin rats for 2 weeks at weeks 4, 8, or 16 after the injection of Adriamycin. A 2-week LPD did not ameliorate kidney damage. Although fibronectin synthesis by the renal cortex in the Adriamycin rats was remarkably reduced by a 2-week LPD, there was no significant decrease in the latent TGF-beta secretion in the Adriamycin rats. The mRNA expressions of fibronectin or TGF-beta 1 were not affected by a 2-week LPD in the Adriamycin rats at any stage. In conclusion, decreased fibronectin and TGF-beta synthesis may be one of the mechanisms by which the long-term dietary protein restriction ameliorates kidney damage. On the other hand, a 2-week LPD affected the only fibronectin synthesis, which thus suggested that an LPD might exert a quicker influence on the protein synthesis of fibronectin than on the transcriptional events of fibronectin.