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: Lisha Liu, Wen Qiu, Hui Wang, Yan Li, Jianbo Zhou, Mei Xia, Kai Shan, Rongrong Pang, Ying Zhou, Dan Zhao, Yingwei Wang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 20 Pg. 16410-23 (May 11 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22427665 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Complement Membrane Attack Complex
• Interferon Regulatory Factor-1
• Irf1 protein, rat
• Isoantibodies
• anti-Thy antibody
• Casp3 protein, rat
• Casp8 protein, rat
• Caspase 3
• Caspase 8

Topics

• Animals
• Apoptosis
• Caspase 3 (genetics, metabolism)
• Caspase 8 (genetics, metabolism)
• Cell Line
• Complement Membrane Attack Complex (genetics, metabolism)
• Disease Models, Animal
• Enzyme Activation (drug effects, genetics)
• Glomerulonephritis, Membranoproliferative (chemically induced, genetics, metabolism, pathology)
• Humans
• Interferon Regulatory Factor-1 (genetics, metabolism)
• Isoantibodies (adverse effects, pharmacology)
• Mesangial Cells (metabolism, pathology)
• Rats
• Response Elements (genetics)