Paricalcitol attenuates TGF‐β1–induced phenotype transition of human peritoneal mesothelial cells (HPMCs)viamodulation of oxidative stress and NLRP3 inflammasome

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‐lβ and IL‐18. Paricalcitol is reported to exert an antiinflammatory 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‐βl‐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 ρrocasρase‐1, with an increased production of IL‐lβ and IL‐18, which was ameliorated by small interfering (si)NLRP3, siASC, caspase inhibitors, or neutralizing antibodies for IL‐lβ and IL‐18. TGF‐βl enhanced reactive oxygen species generation with an increase in NADPH oxidase (NOX) activity and mitochondrial NOX4 production. Paricalcitol alleviated TGF‐βl‐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.—Ko, J., Kang, H.‐J., Kim, D.‐A., Ryu, E.‐S., Yu, M., Lee, H., Lee, H. K., Ryu, H.‐M., Park, S.‐H., Kim, Y.‐L., Kang, D.‐H. Paricalcitol attenuates TGF‐βl–induced phenotype transition of human peritoneal mesothelial cells (HPMCs) via modulation of oxidative stress and NLRP3 inflammasome. FASEB J. 33, 3035–3050 (2019). http://www.fasebj.org

Implications of Oxidative Stress and Potential Role of Mitochondrial Dysfunction in COVID-19: Therapeutic Effects of Vitamin D

“…During peritoneal fibrosis, where the oxidative stress has a crucial role, an epithelial-to-mesenchymal transition of mesothelial cells is produced from peritoneum mediated by TGF-β1. In this sense, paricalcitol reduced the epithelial-to-mesenchymal transition by TGF-β1 through the modulation of oxidative stress associated with mitochondrial production of NOX [94]. In an experimental model of cardiac dysfunction induced by chronic immobilization stress, vitamin D treatment provoked an increase in tissue reserves of glutathione, ATP, SOD, and cardiolipin, which were initially decreased.…”

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

“…Recently, ROS has also been considered to be one of the first identified triggers of NLRP3 inflammasome activation [21], and many chemical compounds were reported to activate NLRP3 inflammasome via increasing intracellular ROS levels [22]. Meanwhile, N-acetyl and P22 (phox), the typical ROS scavengers, could significantly downregulate the NLRP3 inflammasome [23]. Therefore, ROS generation is essential for the activation of the NLRP3 inflammasome.…”

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

“…As an element of epithelial-mesenchymal transition (EMT) of tubular epithelial cells, NLRP3 is associated with tubular atrophy and progressive interstitial fibrosis in CKD (Lorenz et al, 2014). Moreover, TGF-beta induced EMT was associated with an increased protein level of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and pro caspase-1 in human peritoneal mesothelial cells (HPMCs), with an upregulated production of IL-1beta and IL-18, which was inhibited by the gene silencing of NLRP3/ASC with siRNA, caspase inhibitors, or the neutralization of IL-1beta/IL-18 (Ko et al, 2019). Currently, studies on the impact of TGF-betamediated inflammation on renal diseases are mainly focused on hypertension (Felix et al, 2019;Southgate et al, 2019), and reports on TGF-beta-mediated NLRP3 inflammasomes and renal fibrosis are limited.…”