Indoxyl sulfate upregulates the cannabinoid type 1 receptor gene via an ATF3/c-Jun complex-mediated signaling pathway in the model of uremic cardiomyopathy

Yu Juei Hsu, Shih Che Hsu, Yung Lung Chang, Shih Ming Huang, Chun Che Shih, Chien Sung Tsai, Chih Yuan Lin

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: The risk of cardiovascular disease is notably increased in patients with chronic kidney disease (CKD) and cannabinoid receptor type 1 (CB1R) plays an important role in the development of uremic cardiomyopathy. However, the molecular mechanism underlying the uremic toxin-induced upregulation of CB1R remains elusive. Methods: The expression of the ATF3/c-Jun complex and CB1R in both in vivo and in vitro models of CKD were measured. We also determined the impact of the ATF3/c-Jun complex on CB1R expression by transfecting H9c2 cells with dominant negative mutants of ATF3 or c-Jun. Inhibitors of organic anion transport, specific MAPK pathways and oxidative DNA damage were also used to assess the pathways mediating the effects of indoxyl sulfate (IS). Results: CB1R upregulation was associated with increased ATF3 expression and c-Jun phosphorylation in CKD both in vivo and in vitro. Expression of dominant-negative ATF3 or c-Jun mutants in IS-treated cells significantly reduced CB1R mRNA levels. Moreover, Co-IP revealed that the ATF3/c-Jun complex is formed and ChIP confirmed its binding to the CB1R promoter, suggesting that this complex directly stimulates CB1R transcription in CKD. Blocking the cellular entry of IS using an organic anion transport inhibitor, as well as inhibiting the ERK1/2 and/or JNK pathways, abrogated the effects of IS on CB1R, ATF3, and c-Jun expression. The IS-induced reactive oxygen species (ROS) was observed in the mitochondria. Conclusions: We demonstrate that uremic toxins induce ATF3/c-Jun complex-mediated CB1R expression both in vivo and in vitro, possibly by modulating the ERK1/2 and JNK signaling pathways and ROS.

Original languageEnglish
Pages (from-to)128-135
Number of pages8
JournalInternational Journal of Cardiology
Volume252
DOIs
Publication statusPublished - Feb 1 2018
Externally publishedYes

Fingerprint

Indican
Cannabinoid Receptors
Cardiomyopathies
Up-Regulation
Chronic Renal Insufficiency
MAP Kinase Signaling System
Genes
Anions
Reactive Oxygen Species
DNA Damage
Mitochondria
Cardiovascular Diseases
Phosphorylation
Messenger RNA
In Vitro Techniques

Keywords

  • ATF3
  • C-Jun
  • Cannabinoid type 1 receptor
  • Indoxyl sulfate
  • Oxidative stress
  • Uremic cardiomyopathy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Indoxyl sulfate upregulates the cannabinoid type 1 receptor gene via an ATF3/c-Jun complex-mediated signaling pathway in the model of uremic cardiomyopathy. / Hsu, Yu Juei; Hsu, Shih Che; Chang, Yung Lung; Huang, Shih Ming; Shih, Chun Che; Tsai, Chien Sung; Lin, Chih Yuan.

In: International Journal of Cardiology, Vol. 252, 01.02.2018, p. 128-135.

Research output: Contribution to journalArticle

Hsu, Yu Juei ; Hsu, Shih Che ; Chang, Yung Lung ; Huang, Shih Ming ; Shih, Chun Che ; Tsai, Chien Sung ; Lin, Chih Yuan. / Indoxyl sulfate upregulates the cannabinoid type 1 receptor gene via an ATF3/c-Jun complex-mediated signaling pathway in the model of uremic cardiomyopathy. In: International Journal of Cardiology. 2018 ; Vol. 252. pp. 128-135.
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abstract = "Background: The risk of cardiovascular disease is notably increased in patients with chronic kidney disease (CKD) and cannabinoid receptor type 1 (CB1R) plays an important role in the development of uremic cardiomyopathy. However, the molecular mechanism underlying the uremic toxin-induced upregulation of CB1R remains elusive. Methods: The expression of the ATF3/c-Jun complex and CB1R in both in vivo and in vitro models of CKD were measured. We also determined the impact of the ATF3/c-Jun complex on CB1R expression by transfecting H9c2 cells with dominant negative mutants of ATF3 or c-Jun. Inhibitors of organic anion transport, specific MAPK pathways and oxidative DNA damage were also used to assess the pathways mediating the effects of indoxyl sulfate (IS). Results: CB1R upregulation was associated with increased ATF3 expression and c-Jun phosphorylation in CKD both in vivo and in vitro. Expression of dominant-negative ATF3 or c-Jun mutants in IS-treated cells significantly reduced CB1R mRNA levels. Moreover, Co-IP revealed that the ATF3/c-Jun complex is formed and ChIP confirmed its binding to the CB1R promoter, suggesting that this complex directly stimulates CB1R transcription in CKD. Blocking the cellular entry of IS using an organic anion transport inhibitor, as well as inhibiting the ERK1/2 and/or JNK pathways, abrogated the effects of IS on CB1R, ATF3, and c-Jun expression. The IS-induced reactive oxygen species (ROS) was observed in the mitochondria. Conclusions: We demonstrate that uremic toxins induce ATF3/c-Jun complex-mediated CB1R expression both in vivo and in vitro, possibly by modulating the ERK1/2 and JNK signaling pathways and ROS.",
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T1 - Indoxyl sulfate upregulates the cannabinoid type 1 receptor gene via an ATF3/c-Jun complex-mediated signaling pathway in the model of uremic cardiomyopathy

AU - Hsu, Yu Juei

AU - Hsu, Shih Che

AU - Chang, Yung Lung

AU - Huang, Shih Ming

AU - Shih, Chun Che

AU - Tsai, Chien Sung

AU - Lin, Chih Yuan

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Background: The risk of cardiovascular disease is notably increased in patients with chronic kidney disease (CKD) and cannabinoid receptor type 1 (CB1R) plays an important role in the development of uremic cardiomyopathy. However, the molecular mechanism underlying the uremic toxin-induced upregulation of CB1R remains elusive. Methods: The expression of the ATF3/c-Jun complex and CB1R in both in vivo and in vitro models of CKD were measured. We also determined the impact of the ATF3/c-Jun complex on CB1R expression by transfecting H9c2 cells with dominant negative mutants of ATF3 or c-Jun. Inhibitors of organic anion transport, specific MAPK pathways and oxidative DNA damage were also used to assess the pathways mediating the effects of indoxyl sulfate (IS). Results: CB1R upregulation was associated with increased ATF3 expression and c-Jun phosphorylation in CKD both in vivo and in vitro. Expression of dominant-negative ATF3 or c-Jun mutants in IS-treated cells significantly reduced CB1R mRNA levels. Moreover, Co-IP revealed that the ATF3/c-Jun complex is formed and ChIP confirmed its binding to the CB1R promoter, suggesting that this complex directly stimulates CB1R transcription in CKD. Blocking the cellular entry of IS using an organic anion transport inhibitor, as well as inhibiting the ERK1/2 and/or JNK pathways, abrogated the effects of IS on CB1R, ATF3, and c-Jun expression. The IS-induced reactive oxygen species (ROS) was observed in the mitochondria. Conclusions: We demonstrate that uremic toxins induce ATF3/c-Jun complex-mediated CB1R expression both in vivo and in vitro, possibly by modulating the ERK1/2 and JNK signaling pathways and ROS.

AB - Background: The risk of cardiovascular disease is notably increased in patients with chronic kidney disease (CKD) and cannabinoid receptor type 1 (CB1R) plays an important role in the development of uremic cardiomyopathy. However, the molecular mechanism underlying the uremic toxin-induced upregulation of CB1R remains elusive. Methods: The expression of the ATF3/c-Jun complex and CB1R in both in vivo and in vitro models of CKD were measured. We also determined the impact of the ATF3/c-Jun complex on CB1R expression by transfecting H9c2 cells with dominant negative mutants of ATF3 or c-Jun. Inhibitors of organic anion transport, specific MAPK pathways and oxidative DNA damage were also used to assess the pathways mediating the effects of indoxyl sulfate (IS). Results: CB1R upregulation was associated with increased ATF3 expression and c-Jun phosphorylation in CKD both in vivo and in vitro. Expression of dominant-negative ATF3 or c-Jun mutants in IS-treated cells significantly reduced CB1R mRNA levels. Moreover, Co-IP revealed that the ATF3/c-Jun complex is formed and ChIP confirmed its binding to the CB1R promoter, suggesting that this complex directly stimulates CB1R transcription in CKD. Blocking the cellular entry of IS using an organic anion transport inhibitor, as well as inhibiting the ERK1/2 and/or JNK pathways, abrogated the effects of IS on CB1R, ATF3, and c-Jun expression. The IS-induced reactive oxygen species (ROS) was observed in the mitochondria. Conclusions: We demonstrate that uremic toxins induce ATF3/c-Jun complex-mediated CB1R expression both in vivo and in vitro, possibly by modulating the ERK1/2 and JNK signaling pathways and ROS.

KW - ATF3

KW - C-Jun

KW - Cannabinoid type 1 receptor

KW - Indoxyl sulfate

KW - Oxidative stress

KW - Uremic cardiomyopathy

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