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

Liping Sun, Jing Liu, Yanggang Yuan, Inzhou Zhang, Zheng Dong

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F469-F478
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number3
DOIs
StatePublished - Sep 1 2018

Fingerprint

Cisplatin
Proteins
Kidney
Acetylation
Apoptosis
Epigenomics
DNA Damage
Histone Code
Heme Oxygenase-1
p38 Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type II
Non-Small Cell Lung Carcinoma
Histones
Stomach Neoplasms
Weight Loss
Oxidative Stress
Phosphotransferases
Antioxidants
Body Weight
Phosphorylation

Keywords

  • Cisplatin nephrotoxicity
  • DNA damage response
  • JQ1
  • MAPK
  • ROS
  • p53

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity. / Sun, Liping; Liu, Jing; Yuan, Yanggang; Zhang, Inzhou; Dong, Zheng.

In: American Journal of Physiology - Renal Physiology, Vol. 315, No. 3, 01.09.2018, p. F469-F478.

Research output: Contribution to journalArticle

Sun, Liping ; Liu, Jing ; Yuan, Yanggang ; Zhang, Inzhou ; Dong, Zheng. / Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 315, No. 3. pp. F469-F478.
@article{4d9c796b26d24411be3dae42e035924f,
title = "Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity",
abstract = "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 = "Cisplatin nephrotoxicity, DNA damage response, JQ1, MAPK, ROS, p53",
author = "Liping Sun and Jing Liu and Yanggang Yuan and Inzhou Zhang and Zheng Dong",
year = "2018",
month = "9",
day = "1",
doi = "10.1152/ajprenal.00527.2017",
language = "English (US)",
volume = "315",
pages = "F469--F478",
journal = "American Journal of Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "3",

}

TY - JOUR

T1 - Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity

AU - Sun, Liping

AU - Liu, Jing

AU - Yuan, Yanggang

AU - Zhang, Inzhou

AU - Dong, Zheng

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - Cisplatin nephrotoxicity

KW - DNA damage response

KW - JQ1

KW - MAPK

KW - ROS

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=85052950739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052950739&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00527.2017

DO - 10.1152/ajprenal.00527.2017

M3 - Article

VL - 315

SP - F469-F478

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 1931-857X

IS - 3

ER -