A potential adjuvant chemotherapeutics, 18?-glycyrrhetinic acid, inhibits renal tubular epithelial cells apoptosis via enhancing BMP-7 epigenetically through targeting HDAC2.

ABSTRACT: Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by an effective adjuvant via epigenetic modification through targeting HDAC2. Molecular docking and SPR assay firstly reported that 18?GA, major metabolite of GA, could directly bind to HDAC2 and inhibit the activity of HDAC2. The effects and mechanisms of GA and 18?GA were assessed in CP-induced AKI in C57BL/6 mice, and in CP-treated HK-2 and mTEC cells lines. TUNEL and FCM results confirmed that GA and 18?GA could inhibit apoptosis of renal tubular epithelial cells induced by CP in vivo and in vitro. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by 18?GA in AKI models while siRNA BMP-7 could reduce the inhibitory effect of 18?GA on apoptosis. Results of current study indicated that 18?GA inhibited apoptosis of renal tubular epithelial cells via enhancing the level of BMP-7 epigenetically through targeting HDAC2, therefore protecting against CP-induced AKI. These available evidence, which led to an improved understanding of molecular recognition, suggested that 18?GA could serve as a potential clinical adjuvant in chemotherapy.

SUBMITTER: Ma T 

PROVIDER: S-EPMC4857087 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature