Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity

Punithavathi Ranganathan, Rania Hamad, Riyaz Mohamed, Calpurnia Jayakumar, Thangaraju Muthusamy, Ganesan Ramesh

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Cisplatin-induced acute kidney injury is a serious problem in cancer patients during treatment of solid tumors. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Since histone deacetylase (HDAC) inhibition augments cisplatin anti-tumor activity, we tested whether HDAC inhibitors can prevent cisplatin-induced nephrotoxicity and determined the underlying mechanism. Cisplatin upregulated the expression of several HDACs in the kidney. Inhibition of HDAC with clinically used trichostatin A suppressed cisplatin-induced kidney injury, inflammation, and epithelial cell apoptosis. Moreover, trichostatin A upregulated the novel anti-inflammatory protein, activated microglia/macrophage WAP domain protein (AMWAP), in epithelial cells which was enhanced with cisplatin treatment. Interestingly, HDAC1 and -2 specific inhibitors are sufficient to potently upregulate AMWAP in epithelial cells. Administration of recombinant AMWAP or its epithelial cell-specific overexpression reduced cisplatin-induced kidney dysfunction. Moreover, AMWAP treatment suppressed epithelial cell apoptosis, and siRNA-based knockdown of AMWAP expression abolished trichostatin A-mediated suppression of epithelial cell apoptosis in vitro. Thus, HDAC-mediated silencing of AMWAP may contribute to cisplatin nephrotoxicity. Hence, HDAC1 and -2 specific inhibitors or AMWAP could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity.

Original languageEnglish (US)
Pages (from-to)317-326
Number of pages10
JournalKidney International
Volume89
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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Keywords

  • AMWAP
  • acute kidney injury
  • cisplatin
  • histone deacetylases
  • inflammation

ASJC Scopus subject areas

  • Nephrology

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