title: LXR agonist T0901317 upregulates thrombomodulin expression in glomerular endothelial cells by inhibition of nuclear factor‑κB.
abstract: Dysfunction of glomerular endothelial cells (GECs) induces a variety of symptoms, including proteinuria, inflammation, vascular diseases, fibrosis and thrombosis. Thrombomodulin (TM) acts as a vasoprotective molecule on the surface of the vascular endothelial cells to maintain the homeostasis of the endothelial microenvironment by suppressing cellular proliferation, adhesion and inflammatory responses. Liver X receptor (LXR), a nuclear receptor (NR) and a bile acid‑activated transcription factor, regulates metabolism and cholesterol transport, vascular tension and inflammation. Previous studies indicated that TM expression is upregulated by various NRs; however, it is unclear whether pharmacological modulation of LXR may affect TM expression and GEC function. The current study revealed that LXR activation by its agonist, T0901317, upregulates the expression and activity of TM. This effect was mediated specifically through LXR‑α, and not through LXR‑β. Additionally, T0901317 treatment inhibited nuclear factor‑κB (NF‑κB) signaling and the secretion of high glucose‑induced proinflammatory mediators, including tumor necrosis factor‑α and interleukin‑1β in GECs. Co‑immunoprecipitation experiments determined that treatment with T0901317 enhances the interaction between LXR‑α and the transcriptional coactivator, p300, in GEC extracts. The present findings suggest that NF‑κB may be a negative regulator of TM expression, and its removal may contribute to TM gene expression, particularly when in competition with the T0901317‑enhanced formation of the LXR/p300 complex. Therefore, LXR may be a novel molecular target for manipulating TM in GECs, which may advance the treatment of endothelial cell‑associated diseases.
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Hanlu
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Yunlin
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Nephrology, Chengdu Second People's Hospital, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology*; D000071518:Liver X Receptors / Q000819:agonists*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D013449:Sulfonamides / Q000494:pharmacology*; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D016207:Cytokines; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D016328:NF-kappa B; D013449:Sulfonamides; D018180:Thrombomodulin; D050880:p300-CBP Transcription Factors; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides