Nephroprotective effects of ferulic acid, Z-ligustilide and E-ligustilide isolated from Angelica sinensis against cisplatin toxicity in vitro.

Cisplatin (CisPt), a chemotherapeutic drug applied against solid tumors, is highly detrimental to the kidney. The risk of acute kidney injury implies adequate patient hydration to ensure sufficient diuresis; this strategy, now implemented in clinical practice, remains however incompletely satisfactory. New pharmacological approaches relying on the discovery of bioactive compounds need to be developed. Based on previous studies reporting renoprotective activities for extracts of Angelica sinensis (Oliv.) Diels roots, three of its major active compounds, ferulic acid, Z-ligustilide and E-ligustilide, were investigated for possible alleviation of CisPt-induced nephrotoxicity. Five phenomena involved in acute kidney injury and subsequent fibrosis were investigated: (i) modulation of cell survival via reduction of the apoptosis rate; (ii) reduction of oxidative stress; (iii) improvement of tubular regeneration capacities through proliferation and migration; (iv) limitation of extracellular matrix and collagen deposition; and (v) prevention of the dedifferentiation processes via the β-catenin pathway. Ferulic acid emerged as the most potent compound for alleviating cell death and collagen deposition, and for enhancing cell regeneration capacities. It also partially inhibited the β-catenin pathway, but was ineffective in lowering oxidative stress. Z- and E-ligustilides, however, were effective for limiting the oxidative stress, but only moderately affected other parameters. Ferulic acid appears to be a promising nephroprotective drug lead deserving further preclinical investigation.