H1-A extracted from Cordyceps sinensis suppresses the proliferation of human mesangial cells and promotes apoptosis, probably by inhibiting the tyrosine phosphorylation of Bcl-2 and Bcl-XL

Abstract

H1-A, a pure compound used in traditional Chinese medicine, is effective in the treatment of autoimmune disorders of MRL lpr/lpr mice. We have previously reported that after 8 weeks of oral therapy with H1-A, 40 μg/kg/day, MRL lpr/lpr mice demonstrated significantly less proteinuria, lower serum creatinine levels, and less renal mesangial proliferation than mice in an untreated group. To clarify the pharmacologic properties of H1-A, we studied its cellular and subcellular effects in cultured human mesangial cells. Our results show that H1-A inhibits cell proliferation and promotes the apoptosis of interleukin (IL)-1- and platelet-derived growth factor (PDGF)-BB-activated human mesangial cells in vitro. Uptake of tritiated thymidine was nearly totally suppressed by the addition of 12.5 μmol/L H1-A (counts per minute decreased from 3905 ± 70 to 141 ± 5). The population of S-phase cells decreased from 15.5% ± 1.7% to 10.0% ± 0.3%, and G0 + G1 phase cells increased from 68.8% ± 0.07% to 74.6% ± 0.05%. This suppression was not a result of cytotoxicity. Apoptosis of human mesangial cells was detectable after treatment with 12.5 or 25 μmol/L H1-A. Using immunoprecipitation and immunoblotting, we found that H1-A inhibits tyrosine phosphorylation of human mesangial proteins and that Bcl-2 and Bcl-XL were probably among these proteins. These findings suggest that H1-A modulates some subcellular signal-transduction pathways and changes the balance between proliferation and apoptosis of mesangial cells in vitro or in vivo. H1-A may be effective in the management of autoimmune disorders, and the modulation of the signal transduction proteins Bcl-2 and Bcl-XL may represent a target for future pharmacologic interventions.