Abstract
Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by histone deacetylase (HDAC) inhibitors via epigenetic modification to enhance bone morphogenetic protein 7 (BMP-7) expression. Cisplatin upregulated the activity of HDAC2 in the kidney. Inhibition of HDAC with clinically used trichostatin A (TSA) or valproic acid (VPA) suppressed cisplatin-induced kidney injury and epithelial cell apoptosis. Overexpression of HDAC2 promotes CP-treated tubular epithelium cells apoptosis. Chromatin immunoprecipitation assay clearly detected HDAC2 assosiation with BMP-7 promoter. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by TSA or VPA in vivo and in vitro. Interestingly, administration of recombinant BMP-7 (rhBMP-7) reduced cisplatin-induced kidney dysfunction. Moreover, BMP-7 treatment suppressed epithelial cell apoptosis and small interfering RNA-based knockdown of BMP-7 expression abolished HDAC inhibitors suppression of epithelial cell apoptosis in vitro. Results of current study indicated that TSA or VPA inhibited apoptosis of renal tubular epithelial cells via promoting the level of BMP-7 epigenetically through targeting HDAC2. Hence, HDAC inhibitors could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity.
Highlights
Cisplatin (CP), which directly interferences with DNA synthesis and apoptosis, is usually used to treat numerous types of cancers
Abundant evidence shows that apoptotic cell death is a prominent and characteristic feature of acute kidney injury (AKI) caused by nephrotoxic medications.[3]
It is suggested that the potential roles of histone deacetylase (HDAC) inhibitors may be responsible for promoting renal regeneration and functional recovery in AKI induced by CP
Summary
Cisplatin (CP), which directly interferences with DNA synthesis and apoptosis, is usually used to treat numerous types of cancers. Limited understandings of the cellular mechanisms of acute kidney injury (AKI) complicate the development of an effective treatment.[1] Abundant evidence shows that apoptotic cell death is a prominent and characteristic feature of AKI caused by nephrotoxic medications.[3] improved mechanistic understanding of renal cell apoptosis has generated new therapeutic targets in AKI. The protective activities of HDAC inhibitors were mediated through upregulation of a novel antiapoptotic protein called BMP-7 in renal tubular epithelial cells. The study revealed that opposing regulation of BMP-7 contributed to the role of HDAC2 on renal tubular epithelial cell apoptosis
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