title: Cyclopropanyldehydrocostunolide LJ attenuates high glucose-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.
abstract: The aim of this research was to investigate the effects of cyclopropanyldehydrocostunolide (also named LJ), a derivative of sesquiterpene lactones (SLs), on high glucose (HG)-induced podocyte injury and the associated molecular mechanisms.
  
  
  
  Differentiated mouse podocytes were incubated in different treatments. The migration and albumin filtration of podocytes were examined by Transwell filters. The protein and mRNA levels of MCP-1 were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (q-PCR). Protein expression and phosphorylation were detected by western blot, and the nuclear translocation of NF-κB was performed with a confocal microscope. The gene expression of the receptor activator for NF-κB (RANK) was silenced by small interfering RNA (siRNA).
  
  
  
  Our results showed that HG enhanced migration, albumin filtration and MCP-1 expression in podocytes. At the molecular level, HG promoted the phosphorylation of NF-κB/p65, IKKβ, IκBα, mitogen-activated protein kinase (MAPK) and the nuclear translocation of p65. LJ reversed the effects of HG in a dose-dependent manner. Furthermore, our data provided the first demonstration that the receptor activator for NF-κB ligand (RANKL) and its cognate receptor RANK were overexpressed in HG-induced podocytes and were downregulated by LJ. RANK siRNA also attenuated HG-induced podocyte injury and markedly inhibited the activation of NF-κB and MAPK signaling pathways.
  
  
  
  LJ attenuates HG-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liu
authors.affiliation: Department of Gerontology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Yu-Xian
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Du
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Peng
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Zhou
authors.affiliation: Department of Emergency, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China.
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China. Electronic address: longhb1966@163.com.
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Long
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D015415:Biomarkers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D007783:Lactones; D008565:Membrane Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C498144:Rela protein, mouse; D012717:Sesquiterpenes; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D051996:Transcription Factor RelA; C113267:nephrin
keywords: LJ; Mitogen-activated protein kinase; NF-κB; Receptor activator for NF-κB; Receptor activator for NF-κB ligand