Original Article Role of Bcl-xL Induction in HGF-mediated Renal Epithelial Cell Survival after Oxidant Stress
Jinglan Zhang, Junwei Yang and Youhua Liu
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Received 29 Aug 2007; accepted with revision 10 Sept 2007; available online 1 January 2008
Abstract: Hepatocyte growth factor (HGF) is known to promote renal epithelial cell survival by dual mechanisms involving Bad phosphorylation and Bcl-xL induction. However, it remains elusive as to the relative contributions of these two events to HGF-mediated cytoprotection. Here we investigated the role and mechanism of HGF in protecting renal epithelial cells from death induced by oxidant stress both in vitro and in vivo. Simultaneous incubation of human kidney proximal tubular epithelial cells (HKC-8) with HGF failed to protect them from oxidant stress-induced cell death, even though it was capable of inducing endogenous Akt and Bad phosphorylation. However, pre-incubation of HKC-8 cells with HGF for 48 hours dramatically promoted their survival and prevented caspase-3 cleavage and activation induced by H2O2. A close association between Bcl-xL induction and effective cytoprotection by HGF was observed in HKC-8 cells after H2O2 treatment. Furthermore, ectopic expression of exogenous Bcl-xL via adenoviral vector prevented H2O2-triggered caspase-3 activation. In a mouse model of acute kidney injury induced by ischemia/reperfusion, pre-administration of HGF expression vector drastically prevented apoptosis and largely preserved kidney function, whereas much less protective effect was observed when HGF gene was given immediately after ischemic injury. These results suggest that Bcl-xL induction plays an imperative role in mediating HGF cytoprotection of renal epithelial cells after death challenge. (IJCEP708016).
Address all correspondence to: Youhua Liu, Ph.D, Department of Pathology, University of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Tel., 412-648-8253; Fax, 412-648-1916; Email: firstname.lastname@example.org.