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Involvement of endoplasmic reticulum stress in angiotensin II-induced NLRP3 inflammasome activation in human renal proximal tubular cells in vitro.

Abstract：

AIM:NLRP3 inflammasome plays an important role in renal injury and may be a therapeutic target in the treatment of patients with progressive chronic kidney disease. In this study we investigated whether angiotensin II (Ang II)-induced NLRP3 inflammasome activation was linked to endoplasmic reticulum stress (ERS) in human renal proximal tubular cells in vitro. METHODS:Human kidney proximal epithelial cells (HK-2) were pretreated with telmisartan or 4-PBA, and then treated with Ang II. The expression levels of mRNAs and proteins related to NLRP3 inflammasomes and ERS was examined by real-time PCR, Western blot and immunofluorescence. RESULTS:Treatment with Ang II (10, 100, and 1000 nmol/L) increased the expression of the inflammasome markers NLRP3 and ASC, as well as caspase-1, IL-1β, and IL-18 in dose- and time-dependent manners with peak levels detected at 100 nmol/L and 12 h. Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18 were significantly reduced by pretreatment with telmisartan (1 μmol/L). Immunofluorescence studies showed that Ang II increased the expression of NLRP3 and ASC, which was inhibited by telmisartan. Furthermore, Ang II treatment increased the expression of ERS markers GRP78 and p-eIF2α in dose- and time-dependent manners, which was significantly reduced by telmisartan. Moreover, Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18 were significantly inhibited by pretreatment with the ERS inhibitor 4-PBA (5 mmol/L). CONCLUSION:Ang II treatment induces NLRP3 inflammasome activation in HK-2 cells in vitro and ER stress is involved in this process, which may represent a new mechanism for the renal rennin-angiotensin system to induce tubulointerstitial inflammation.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Wang J,Wen Y,Lv LL,Liu H,Tang RN,Ma KL,Liu BC

doi

10.1038/aps.2015.21

subject

Has Abstract

pub_date

2015-07-01 00:00:00

pages

821-30

issue

eissn

1671-4083

issn

1745-7254

pii

aps201521

journal_volume

pub_type

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Involvement of endoplasmic reticulum stress in angiotensin II-induced NLRP3 inflammasome activation in human renal proximal tubular cells in vitro.