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Knockdown of Fibronectin Induces Mitochondria-Dependent Apoptosis in Rat Mesangial Cells

Di Wu^*, XiangMei Chen^*, DengFu Guo, Quan Hong^*, Bo Fu^*, Rui Ding^*, LiFang Yu^*, Kai Hou^*, Zhe Feng^*, XiaoJie Zhang^* and JianZhong Wang^*

^* Department of Nephrology, Kidney Center, and Key Laboratory of the People’s Liberty Army (PLA), General Hospital of PLA, Beijing, People’s Republic of China; and Department of Medicine, University of Montreal and Research Centre, Centre Hospitalier de l’Universite de Montreal, Hotel-Dieu, Montreal, Quebec, Canada

Address correspondence to: Dr. XiangMei Chen, Department of Nephrology, Kidney Center and Key Laboratory of PLA, General Hospital of PLA, 28 Fuxing Road, Beijing 100853, China. Phone: 86-10-66935462; Fax: 86-10-68130297; E-mail: xmchen{at}public.bta.net.cn

Extracellular matrix (ECM) expansion and mesangial cell (MC) proliferation are prominent features of most types of glomerulosclerosis. A delicate balance between the ECM and MC regulates cell survival. Increasing evidence shows that a loss of ECM components can cause mitochondrial dysfunction and induce cell apoptosis. It is proposed that directly blocking the synthesis of ECM components could lighten ECM accumulation and suppress cell overproliferation status. Fibronectin, one of the predominant adhesive glycoproteins of the mesangial ECM, provides the survival signal for cells. Its accumulation can be observed in most types of glomerulosclerosis. In this study, angiotensin II–induced fibronectin was suppressed by an RNA interference technique. It is interesting that MC slowly underwent apoptosis after infection with a retrovirus that continuously suppressed fibronectin synthesis. It was found that MC apoptosis occurred in a mitochondria-dependent manner mainly as a result of cytochrome c release and downstream caspase-3 and -9 activation. Furthermore, it was demonstrated that fibronectin knockdown affected mitochondrial handling of Ca²⁺ release from the endoplasmic reticulum. Importantly, blocking the inositol 1,4,5-triphosphate receptor with, 3,4,5-trimethoxybenzoate or decreasing Ca²⁺ in the ECM with EGTA partially saved the cells from apoptosis. These studies, which explored a new method for simultaneously inhibiting MC proliferation and ECM accumulation, may represent a novel therapeutic approach to glomerulosclerosis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673