The Role of Annexin A5 in Cisplatin-induced Toxicity in Renal Cells: the Molecular Mechanism of Apoptosis [Cell Biology]

December 6th, 2013 by Jeong, J.-J., Park, N., Kwon, Y.-J., Ye, D.-J., Moon, A., Chun, Y.-J.

Annexin A5 belongs to a large family of calcium-binding and phospholipid-binding proteins and may act as an endogenous regulator of various pathophysiological processes. There is increasing evidence that annexin A5 is related to cytotoxicity, but the precise function of this protein has yet to be elucidated. This study aims to verify the function of annexin A5 in the apoptosis of renal epithelial cells. Real time-PCR and Western blot analysis, together with immunofluorescence analysis, showed that the expression of annexin A5 significantly increased in the presence of cisplatin in both human and rat renal epithelial cells. In regards to the mechanism of cisplatin-induced apoptosis, AIF release into the cytosol was observed, and the underlying mechanism was identified as VDAC oligomerization. Mitochondrial membrane potential (Δψm) was found to be greatly disrupted in cisplatin-treated cells. Moreover, cisplatin strongly induces translocation of annexin A5 into mitochondria. To understand the functional significance of annexin A5 in renal cell death, we used a small interfering RNA-mediated approach to knockdown annexin A5. Annexin A5 depletion by siRNA led to decreased annexin A5 translocation into mitochondria and significantly reduced VDAC oligomerization and AIF release. Annexin A5 siRNA also increased cell viability compared with the control. Moreover, expression of annexin A5 was also induced by other nephrotoxicants such as CdCl2 or bacitracin. Taken together, our data suggests that annexin A5 may play a crucial role in cisplatin-induced toxicity by mediating the mitochondrial apoptotic pathway via the induction and oligomerization of VDAC.