IJCEP Copyright © 2007-All rights reserved.
Int J Clin Exp Pathol 1(3):242-253;2008

Original Article
Role of Bcl-xL Induction in HGF-mediated Renal Epithelial Cell Survival after Oxidant

Jinglan Zhang, Junwei Yang and Youhua Liu

Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,

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.

Key Words: HGF; c-met; Bcl-xL; apoptosis; Bad; ischemia/reperfusion; acute kidney injury.

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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: