Inhibition of PTK Pa t hway by Genistein in Diabetic Rat

ABSTRACT

The objective of this study is to determine if the elevated retinal levels of phosphotyrosine in the Zucker diabetic fatty rats can be reduced by systemic administration of genistein,a protein tyrosine kinase inhibitor. Sixteen male Zucker diabetic fatty rats were compared with sixteen malelean litter mates as a control. Rats were injected intraperitoneally with 13.6mg/kg B.Wt.of genistein (treated group) or dimethyl sulfoxide (DMSO)(non-treated group) twice two hours apart. Twenty four hours later, the retinas were processed for western blot analysis and immunohistochemical study. The Zucker diabetic fatty rats were found to have increased levels of phosphotyrosine as compared with the lean controls. Intraperitoneal administration of genistein strongly inhibited protein tyrosine phosphorylation in the diabetic rats.Genistein also inhibited the increase in PCNA,but this was less obvious than the decrease in phosphotyrosine. In the diabetic rats, the levels of activated PI3-K and MAPK were increased over control rats. Genistein reduced the levels of PI3-K and MAPK. Immunohistochemical studies of the retina showed decreased immunopositive reaction of PCNA in the retina of the diabetic rats treated with genistein. In conclusion, elevat-ed levels of phospotyrosine in the Zucker diabetic rats can be reduced by systemic administration of genistein. Genistein also reduced, although less, the levels of PCNA and activated forms of PI3-K and MAPK. Our results suggest that PTK inhibitor like genistein may find a role in the reduction of proliferative complications of diabetes mellitus.