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

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.

journal_name

Int J Cardiol

journal_title

International journal of cardiology

authors

Hsu YJ,Hsu SC,Chang YL,Huang SM,Shih CC,Tsai CS,Lin CY

doi

10.1016/j.ijcard.2017.11.086

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

128-135

eissn

0167-5273

issn

1874-1754

pii

S0167-5273(17)34436-4

journal_volume

252

pub_type

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