title: Probucol inhibits JAK2-STAT pathway activation and protects human glomerular mesangial cells from tert-butyl hydroperoxide induced premature senescence.
abstract: Human mesangial cells (HMCs) have a finite lifespan and eventually enter irreversible growth arrest known as cellular senescence, which is thought to contribute to kidney ageing and age-related kidney disorders such as chronic kidney disease. The JAK2-STAT pathway plays a pivotal role in transmitting cytokine signals, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMC senescence still remains to be explored. In our study, tert-butyl hydroperoxide (tBHP)-induced cells accelerated HMC senescence, as judged by increased senescence-associated β-galactosidase stained positive cells, morphological changes, and G0-G1 cell cycle arrest. STAT1 and STAT3 activity were increased in tBHP-induced cells. After tBHP treatment, Bcl-2 protein expression decreased and Bax protein expression increased. Blocking the JAK2-STAT pathway with AG490 and using probucol significantly inhibited the progression of HMC senescence. Bax protein expression decreased, but Bcl-2 protein expression increased after AG490 and probucol treatment. Our results indicated that the JAK2-STAT pathway might mediate tBHP-induced HMC senescence through the Bcl-2-Bax pathway, and that probucol could attenuate HMC senescence by regulating STATs.
authors.affiliation: Department of Nephrology, First Affiliated Hospital of Liaoning Medical College, No. 2, Section 5, RenMin Street, Guta District, Jinzhou City, Liaoning Province 121001, P. R. China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Yarong
authors.initials: Y
authors.lastname: Han
authors.forename: Ruixia
authors.initials: R
authors.lastname: Jin
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D011341:Probucol / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000633:toxicity*
chemical_list: C494826:BAX protein, human; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051028:bcl-2-Associated X Protein; D020122:tert-Butylhydroperoxide; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D001616:beta-Galactosidase; D011341:Probucol