Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity

Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F469-F478. doi: 10.1152/ajprenal.00527.2017. Epub 2018 May 16.


As a potent chemotherapy drug, cisplatin is also notorious for its side-effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extraterminal (BET) proteins are "readers" of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin-induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis. JQ1 also partially prevented the body weight loss during cisplatin treatment in mice. Consistently, JQ1 inhibited cisplatin-induced apoptosis in renal proximal tubular cells. Mechanistically, JQ1 suppressed cisplatin-induced phosphorylation or activation of p53 and Chk2, key events in DNA damage response. JQ1 also attenuated cisplatin-induced MAP kinase (p38, ERK1/2, and JNK) activation. In addition, JQ1 enhanced the expression of antioxidant genes including nuclear factor erythroid 2-related factor 2 and heme oxygenase-1, while diminishing the expression of the nitrosative protein inducible nitric oxide synthase. JQ1 did not suppress cisplatin-induced apoptosis in A549 nonsmall cell lung cancer cells and AGS gastric cancer cells. These results suggest that JQ1 may protect against cisplatin nephrotoxicity by suppressing DNA damage response, p53, MAP kinases, and oxidative/nitrosative stress pathways.

Keywords: DNA damage response; JQ1; MAPK; ROS; cisplatin nephrotoxicity; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects*
  • Azepines / pharmacology*
  • Checkpoint Kinase 2 / metabolism
  • Cisplatin*
  • Cytoprotection
  • DNA Damage / drug effects
  • Disease Models, Animal
  • Enzyme Activation
  • Humans
  • Kidney Diseases / chemically induced
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Diseases / prevention & control*
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Kidney Tubules, Proximal / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitrosative Stress / drug effects
  • Oxidative Stress / drug effects*
  • Phosphorylation
  • Signal Transduction / drug effects
  • Triazoles / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism
  • Weight Loss / drug effects


  • (+)-JQ1 compound
  • Antioxidants
  • Azepines
  • Triazoles
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Checkpoint Kinase 2
  • Chek2 protein, mouse
  • Mitogen-Activated Protein Kinases
  • Cisplatin