Hepatocyte Growth Factor Protects Renal Epithelial Cells from Apoptotic Cell Death

1998 ◽  
Vol 246 (3) ◽  
pp. 821-826 ◽  
Author(s):  
Youhua Liu ◽  
Adam M. Sun ◽  
Lance D. Dworkin
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Renal Epithelial Cells ◽  
Hepatocyte Growth

Hepatocyte growth factor stimulates phosphoinositide hydrolysis and mitogenesis in cultured renal epithelial cells

Life Sciences ◽  
1993 ◽  
Vol 52 (13) ◽  
pp. 1091-1100 ◽  
Author(s):  
Raymond C. Harris ◽  
Kevin D. Burns ◽  
Maha Alattar ◽  
Toshio Homma ◽  
Toshikazu Nakamura
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Phosphoinositide Hydrolysis ◽  
Renal Epithelial Cells ◽  
Hepatocyte Growth

scholarly journals Single Injection of Naked Plasmid Encoding Hepatocyte Growth Factor Prevents Cell Death and Ameliorates Acute Renal Failure in Mice

2002 ◽  
Vol 13 (2) ◽  
pp. 411-422 ◽  
Author(s):  
Chunsun Dai ◽  
Junwei Yang ◽  
Youhua Liu
Keyword(s):  
Renal Failure ◽  
Cell Death ◽  
Acute Renal Failure ◽  
Folic Acid ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Intravenous Injection ◽  
Naked Plasmid ◽  
Hepatocyte Growth

ABSTRACT. Hepatocyte growth factor (HGF) is a pleiotrophic factor that plays an important role in tissue repair and regeneration after injury. The expression of both HGF and its c-met receptor genes is rapidly upregulated after acute renal injury induced by folic acid. In this study, the role of exogenous HGF in preventing acute renal failure by systemic administration of naked plasmid containing human HGF cDNA driven under the cytomegalovirus promoter (pCMV-HGF) was examined in mice. Intravenous injection of pCMV-HGF plasmid produced substantial levels of human HGF protein in mouse kidneys. Simultaneous injection of HGF plasmid DNA significantly ameliorated renal dysfunctions and accelerated recovery from the acute injury induced by folic acid. Of interest, preadministration of HGF plasmid 24 h before folic acid injection dramatically protected renal epithelial cells from both apoptotic and necrotic death and preserved the structural and functional integrity of renal tubules. Expression of HGF transgene activated protein kinase B/Akt kinase and preserved prosurvival Bcl-xL protein expression in vivo. These results indicate that a single, intravenous injection of naked plasmid containing HGF gene not only promotes renal regeneration after injury but also protects tubular epithelial cells from the initial injury and cell death in the first place. These data suggest that HGF gene therapy may provide a new avenue for exploring a novel therapeutic strategy for clinical acute renal failure.

scholarly journals Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta

1997 ◽  
Vol 11 (15) ◽  
pp. 1938-1948 ◽  
Author(s):  
M. Moser ◽  
A. Pscherer ◽  
C. Roth ◽  
J. Becker ◽  
G. Mucher ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Renal Epithelial Cells

Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms

1999 ◽  
Vol 277 (4) ◽  
pp. F624-F633 ◽  
Author(s):  
Youhua Liu
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Constitutive Expression ◽  
Renal Epithelial Cell ◽  
Prolonged Incubation ◽  
Renal Epithelial Cells ◽  
Apoptotic Death ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) has been shown to protect renal epithelial cells against apoptosis. To define the mechanism by which HGF inhibits apoptosis, we investigated the effect of HGF on the phosphorylation and expression of the Bcl-2 family proteins. Using a human proximal tubular epithelial cell (HKC) line as a model, we demonstrated that constitutive expression of HGF conveyed marked resistance to apoptotic death induced by serum withdrawal. HGF induced rapid phosphorylation of Akt in HKC cells, which was immediately followed by phosphorylation and resultant inactivation of Bad, a pro-apoptotic member of the Bcl-2 family. Pretreatment of the HKC cells with 10 nM wortmannin completely abolished HGF-induced phosphorylation of Akt and Bad, suggesting that this pathway is dependent on phosphoinositide (PI) 3-kinase. Overexpression of Bad increased apoptotic death in wild-type HKC cells but not in HGF-producing H4 cells. Immunoblotting confirmed that the Bad protein over-expressed in H4 cells was fully phosphorylated at both Ser112 and Ser136 sites. Prolonged incubation of HKC cells with HGF also dramatically induced expression of Bcl-xL, an anti-apoptotic member of the Bcl-2 family. These results suggest that the anti-apoptotic effect of HGF in renal epithelial cells is mediated by dual mechanisms involving two distinct Bcl-2 family proteins. HGF triggers Bad phosphorylation via the PI 3-kinase/Akt pathway, thereby inactivating this pro-apoptotic protein, while simultaneously inducing expression of anti-apoptotic Bcl-xL.

scholarly journals Hepatocyte Growth Factor Induces MAPK-Dependent Formin IV Translocation in Renal Epithelial Cells

2000 ◽  
Vol 11 (12) ◽  
pp. 2212-2221
Author(s):  
DAWN A. O'ROURKE ◽  
ZHEN-XIANG LIU ◽  
LORENZ SELLIN ◽  
KATHERINE SPOKES ◽  
ROLF ZELLER ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Tubule Formation ◽  
Renal Epithelial Cells ◽  
Mitogen Activated Protein ◽  
Hepatocyte Growth

Abstract. Renal epithelial tubule formation in cultured cells occurs after the addition of tubulogenic growth factors such as the hepatocyte growth factor (HGF). HGF activates the tyrosine kinase receptor c-met, initiating a series of complex events that regulate cell morphology, cell—cell interactions, and cell—matrix interactions and eventually result in the formation of branching tubular structures. The discovery that disruption of the formin gene locus in mice causes agenesis of the kidneys secondary to failure of ureteric bud outgrowth and branching tubule formation suggested that this family of proteins may be critical to the development of renal epithelial tubules. In this study, we investigated whether formin is involved in the HGF/c-met signaling pathway of in vitro tubulogenesis in renal epithelial cells. mIMCD-3 cells were analyzed by reverse transcription-PCR and found to express formin IV mRNA. With the use of an antibody that recognizes the carboxy terminus of all known formin isoforms, it was observed a formin isoform of approximately 165 kD markedly increased in the detergent soluble cell lysate after 10 min of stimulation with HGF. An antibody that is specific for formin IV was then generated and confirmed that the formin isoform regulated by HGF was formin IV. Cell fractionation and confocal localization of formin IV revealed that formin IV is primarily found in a submembranous band that co-localizes with the actin cytoskeleton and in a perinuclear location in quiescent epithelial cells but undergoes a rapid relocalization after HGF stimulation with translocation into the cell cytosol and into the nucleus. Formin IV was found to be a phosphorylation substrate for activated extracellular signal-regulated kinase in vitro, and pretreatment of cells with the mitogen-activated protein kinase inhibitor U0126 prevented the translocation of formin IV and inhibited HGF-dependent phosphorylation of formin IV in intact cells. In conclusion, activation of the c-met receptor results in cellular relocalization of formin IV in a mitogen-activated protein kinase—dependent manner.

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