title: Sublytic C5b-9 complexes induce apoptosis of glomerular mesangial cells in rats with Thy-1 nephritis through role of interferon regulatory factor-1-dependent caspase 8 activation.
abstract: The apoptosis of glomerular mesangial cells (GMC) in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by sublytic C5b-9 deposition, but the mechanism of sublytic C5b-9-mediated GMC apoptosis has not been elucidated. In the present study, the gene expression profiles both in the GMC stimulated by sublytic C5b-9 and the rat renal tissue of Thy-1N were detected using microarrays. Among the co-up-regulated genes, the up-regulation of interferon regulatory factor-1 (IRF-1) was further confirmed. Increased caspase 8 and caspase 3 expression and caspase 8 promoter activity in the GMC were also identified. Meanwhile, overexpression or knockdown of IRF-1 not only enhanced or inhibited GMC apoptosis and caspase 8 and 3 induction but also increased or decreased caspase 8 promoter activity, respectively. The element of IRF-1 binding to the caspase 8 promoter was first revealed. Furthermore, silencing IRF-1 or repressing the activation of caspases 8 and 3 significantly reduced GMC apoptosis, including other pathologic changes of Thy-1N. These novel findings indicate that GMC apoptosis of Thy-1N is associated with the IRF-1-activated caspase 8 pathway.
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Liu
authors.forename: Wen
authors.initials: W
authors.lastname: Qiu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jianbo
authors.initials: J
authors.lastname: Zhou
authors.forename: Mei
authors.initials: M
authors.lastname: Xia
authors.forename: Kai
authors.initials: K
authors.lastname: Shan
authors.forename: Rongrong
authors.initials: R
authors.lastname: Pang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007518:Isoantibodies / Q000009:adverse effects / Q000494:pharmacology; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020218:Response Elements / Q000235:genetics
chemical_list: D015938:Complement Membrane Attack Complex; D050856:Interferon Regulatory Factor-1; C494259:Irf1 protein, rat; D007518:Isoantibodies; C035678:anti-Thy antibody; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; D053148:Caspase 3; D053181:Caspase 8