Yingwei Wang
YuNanjing Medical University, China
Title: Sublytic C5b-9 induces glomerular mesangial cell apoptosis through the cascade pathway of MEKK2-p38 MAPK-IRF-1-TRADD-caspase 8 in rat Thy-1 nephritis
Biography
Biography: Yingwei Wang
Abstract
The apoptosis of glomerular mesangial cell (GMC) in the early phase of rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is mainly triggered by sublytic C5b-9. But the mechanism of GMC apoptosis induced by sublytic C5b-9 remains unclear. In current study, we demonstrated that the expression of TNFR1-associated death domain-containing protein (TRADD) and interferon regulatory factor-1 (IRF-1) was simultaneously up-regulated both in the renal tissue of Thy-1N rats (in vivo) and in the GMC under sublytic C5b-9 stimulation (in vitro). And in vitro, TRADD was confirmed to be a downstream gene of IRF-1 because IRF-1 could bind to TRADD gene promoter to promote its transcription, leading to caspase 8 activation and GMC apoptosis. Meanwhile, increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was verified to contribute to IRF-1 and TRADD production and caspase 8 activation as well as GMC apoptosis treated by sublytic C5b-9. Furthermore, the phosphorylation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) was found to mediate p38 MAPK activation. More importantly, three sites (Ser-153/164/239) of MEKK2 phosphorylation were first identified and demonstrated to be necessary for p38 MAPK activation. Besides, silence of renal MEKK2, IRF-1 and TRADD gene or inhibition of p38 MAPK activation in vivo displayed obvious inhibitory effects on GMC apoptosis, secondary proliferation and urinary protein secretion in rats with Thy-1N. Collectively, these findings indicate that the cascade axis of MEKK2-p38 MAPK-IRF-1-TRADD-caspase 8 may play an important role in GMC apoptosis following exposure to the sublytic C5b-9 in rat Thy-1N.