Paricalcitol attenuates TGF-b1-induced phenotype transition of human peritoneal mesothelial cells (HPMCs) via modulation of oxidative stress and NLRP3 inflammasome

Jiyeon Ko, Hyun Jung Kang, Dal Ah Kim, Eun Sun Ryu, Mina Yu, Huisong Lee, Hyeon Kook Lee, Hye Myung Ryu, Sun Hee Park, Yong Lim Kim, Duk Hee Kang

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Phenotype transition of mesothelial cells, such as epithelial-to-mesenchymal transition (EMT), is one of the early mechanisms of peritoneal fibrosis, which is mediated by oxidative stress and inflammation. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein oligomer that promotes the maturation of IL-1β and IL-18. Paricalcitol is reported to exert an anti-inflammatory effect; however, there are no studies as to whether paricalcitol modulates the activation of NLRP3 inflammasome. We investigated the role of NLRP3 inflammasome in peritoneal EMT with an exploration of the effect of paricalcitol on oxidative stress, NLRP3 inflammasome, and EMT of mesothelial cells. TGF-β1-induced EMT in human peritoneal mesothelial cells (HPMCs) was associated with an up-regulation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and procaspase-1, with an increased production of IL-1β and IL-18, which was ameliorated by small interfering (si)NLRP3, siASC, caspase inhibitors, or neutralizing antibodies for IL-1β and IL-18. TGF-β1 enhanced reactive oxygen species generation with an increase in NADPH oxidase (NOX) activity and mitochondrial NOX4 production. Paricalcitol alleviated TGF-β1-induced EMT and the NLRP3 inflammasome, which was associated with a down-regulation of NOX activity by interfering with p47phox and p22phox interaction and mitochondrial NOX4 production in HPMCs. Taken together, paricalcitol ameliorated EMT of HPMCs via modulating an NOX-dependent increase in the activity of NLRP3 inflammasome. Paricalcitol could be a novel approach to protect the peritoneum from the development of EMT and peritoneal fibrosis.

Original languageEnglish
Pages (from-to)3035-3050
Number of pages16
JournalFASEB Journal
Volume33
Issue number2
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by the Korean Health Technology Research and Development Project (Ministry of Health and Welfare, Republic of Korea Grants HI12C0050, HI15C0001, and HC15C1129); a National Research Foundation of Korea (NRF) grant funded by the Korean government [Ministry of Science and Information and Communications Technology (MSIT); NRF-2015R1A2A1A15053374 and NRF-2017R1A2B2005849]; and the Ewha Womans University Research Grant of 2016. The authors declare no conflicts of interest.

Publisher Copyright:
© FASEB.

Keywords

  • EMT
  • NADPH oxidase
  • Peritoneal dialysis
  • Peritoneal fibrosis
  • Vitamin D agonist

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