In vitro effects of Panax ginseng in aristolochic acid-mediated renal tubulotoxicity: apoptosis versus regeneration

This in vitro study aims at determining the effects of a Panax ginseng C.A Meyer extract (PG) on aristolochic acid (AA) mediated toxicity in HK-2 cells. A methanolic extract of ginseng (50 µg/mL) was able to reduce cell survival after treatment with 50 µM AA for 24, 48 and 72 hours, as evidenced by a resazurin reduction assay. This result was confirmed by flow cytometric evaluation of apoptosis using annexin V-PI staining, and indicated higher apoptosis rates in cells treated with AA and PG compared with AA alone. However, PG by itself (5 and 50 µg/mL) increased the Ki-67 index, indicating an enhancement in cellular proliferation. Cell cycle analysis excluded a PG-mediated induction of G2/M cell cycle arrest such as the one typically observed with AA. Finally, β-catenin acquisition was found to be accelerated when cells were treated with both doses of ginseng, suggesting that the epithelial phenotype of RPTECs was maintained. Also, ginseng treatment (5 and 50 µg/mL) reduced the oxidative stress activity induced by AA after 24 and 48 hours.
These results indicate that the ginseng extract has a protective activity towards the generation of cytotoxic reactive oxygen species induced by AA. However, the ginseng-mediated alleviation of oxidative stress did not correlate with a decrease but rather with an increase in AA-induced apoptosis and death. This deleterious herb-herb interaction could worsen AA tubulotoxicity and reinforce the severity and duration of the injury. Nevertheless, increased cellular proliferation and migration, along with the improvement in the epithelial phenotype maintenance, indicate that ginseng could be useful for improving tubular regeneration and the recovery following drug-induced kidney injury. Such dual activities of ginseng certainly warrant further in vivo studies.