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

17 Citations (Scopus)

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
StatePublished - Feb 1 2016

Fingerprint

Histone Deacetylases
Microglia
Cisplatin
Macrophages
trichostatin A
Epithelial Cells
Apoptosis
Kidney
Protein Domains
Therapeutics
Neoplasms
Histone Deacetylase Inhibitors
Acute Kidney Injury
Small Interfering RNA
Anti-Inflammatory Agents
Up-Regulation
Inflammation

Keywords

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

ASJC Scopus subject areas

  • Nephrology

Cite this

Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. / Ranganathan, Punithavathi; Hamad, Rania; Mohamed, Riyaz; Jayakumar, Calpurnia; Muthusamy, Thangaraju; Ramesh, Ganesan.

In: Kidney International, Vol. 89, No. 2, 01.02.2016, p. 317-326.

Research output: Contribution to journalArticle

Ranganathan, Punithavathi ; Hamad, Rania ; Mohamed, Riyaz ; Jayakumar, Calpurnia ; Muthusamy, Thangaraju ; Ramesh, Ganesan. / Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. In: Kidney International. 2016 ; Vol. 89, No. 2. pp. 317-326.
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