Computational and experimental characterization of isomers of escin-induced renal cytotoxicity by inhibiting heat shock proteins

Abstract

Escin is a natural mixture of triterpene saponins, exhibits anti-oedematous properties and promotes venous drainage by oral administration or injection. Upon clinical application of escin, adverse kidney reactions have been reported and the nephrotoxic mechanism responsible for this reaction remains elusive. In the present study, four isomeric escins (β-form: escin Ia and escin Ib; α-form: isoescin Ia and isoescin Ib) were found severely decreasing the cell viability of human kidney (HK-2) cells. A decline in HK-2 cell viability caused by sodium aescinate (a mixture of four isomers) was reduced after β-glucuronidase hydrolysis. In addition, sodium aescinate concentration-dependently inhibited the expression level of heat shock proteins (HSPs) in the Madin-Darby Canine Kidney (MDCK) cells. Moreover, with molecular docking and molecular dynamics simulation, these four isomeric escins could directly bind to the ATP-binding domain of HSP70 and HSP90, thus competitively inhibiting the function of HSPs. Escin Ia is bound to HSPs with the lowest binding free energy, which is consistent with the observation that escin Ia most severely decreases HK-2 cell viability. Thus, we demonstrate a heretofore unknown molecular mechanism of escin-induced renal cytotoxicity as well as identify HSPs as potential targets for the renal cytotoxic effect of escin.